Abstract
Background
Posttransplant cytomegalovirus (PT-CMV) infection remains a challenging complication and a major cause of morbidity and mortality in transplant recipients.
Methods
This cross-sectional study surveyed physicians treating solid organ and hematopoietic stem cell transplantation recipients from Central and Eastern European countries. Physician-reported CMV infection prevalence in transplant recipients, treatment regimens, and unmet needs for managing patients with refractory with/without resistance (R+/R-) PT-CMV infection were assessed.
Results
Overall, 164 physicians completed the survey, 23.8% of whom were nephrologists. Physicians estimated that 26.4% of patients who received a transplant in the past 12 months developed PT-CMV infection, of whom 12.9% had refractory R+/R- PT-CMV infection. On average, 66.5%, 16.5%, and 4.0% of physicians’ current patients with PT-CMV infection received first-, second-, and third- or later-line treatments, respectively. Physicians considered maintenance of CMV viremia clearance (94.5%), good symptom control (94.5%), and lack of renal toxicity (93.9%) as moderately-to-extremely important treatment attributes for managing PT-CMV infection. Compared with other available treatments, more physicians indicated oral valganciclovir to have a strong-to-complete association with these treatment attributes. Overall, 63.4% of physicians indicated some level of satisfaction with conventional refractory R+/R- PT-CMV treatments. However, 54.9% of physicians reported limited experience with newly approved therapies, such as maribavir. Most physicians considered limited treatment options as a major barrier for improving patient outcomes.
Conclusion
Survey findings of physicians treating transplant recipients in Central and Eastern Europe suggest the need for increased awareness of newly approved therapies with better efficacy and less toxicity for refractory R+/R- PT-CMV infection.
Keywords
Key summary points
• Posttransplant cytomegalovirus (PT-CMV) infection remains a challenging complication and a major cause of morbidity and mortality in transplant recipients. • The study aimed to estimate the prevalence of refractory CMV infection in transplant recipients over the past 12 months in Central and Eastern Europe and assess current treatment modalities, challenges, and unmet needs for managing these patients. • The survey found that 26.4% of transplant recipients developed PT-CMV infection in the past 12 months, with 12.9% of these cases being refractory R+/R- PT-CMV infection. • The findings suggest a need for increased awareness of newly approved therapies with better efficacy and less toxicity for refractory R+/R- PT-CMV infection.
1. Introduction
Cytomegalovirus (CMV) is a ubiquitous DNA virus belonging to the Herpesviridae family and is prevalent in approximately 100% of the population in Africa and Asia and 80% in Europe and North America.1–3 In transplant recipients, CMV infection can occur due to transmission from the transplanted organ, reactivation of the latent infection, or as a new primary infection in seronegative patients. 4 Globally, prevalence rates of CMV infection in recipients ranged from 6%–56% in solid organ transplant (SOT)5–9 recipients and approximately 25%–61% within 1 year of allogeneic hematopoietic stem cell transplantation (HSCT). 10 Direct effects of CMV infection in transplant recipients can range from asymptomatic viremia to invasive diseases such as colitis and pneumonitis, bacterial and fungal infections, and reduced graft survival and failure. 11 Posttransplant (PT) CMV infection is thus a major cause of morbidity and mortality in allogeneic HSCT and SOT recipients.12,13
The most effective approaches to preventing posttransplant CMV infection are antiviral prophylaxis and pre-emptive treatment. 14 However, discussions from a panel of experts at the 2023 International CMV Symposium highlighted that despite progress in treatment and diagnostics resulting in substantial benefit on patient outcomes, the management of CMV infection remains complicated. 15 This is mainly due to the emergence of drug-resistant viral mutations, latency, and toxicities and resistance associated with conventional antiviral treatments.16–18 Moreover, even with advances in preventive strategies, patients who are exposed to immunosuppressive therapy are at a high risk of developing CMV infection, severe CMV-related disease, and graft rejection. 19 The international consensus guidelines on the management of CMV in solid organ transplantation provide a comprehensive, scientific, evidence-based framework, ranging from understanding host–viral dynamics to formulating optimal preventive and therapeutic methodologies.20,21 The recommended standard first-line antiviral drug for CMV prevention and treatment is intravenous (IV) ganciclovir or its oral prodrug, valganciclovir. Foscarnet and cidofovir are used as second-line treatments. However, these treatments are associated with severe adverse events such as nephrotoxicity (foscarnet and cidofovir) and myelosuppression (ganciclovir, valganciclovir, foscarnet, and cidofovir).22,23 Treatment-related toxicities are a major cause of treatment discontinuation that negatively impact patient outcomes. 10 For instance, a high incidence of CMV viremia was reported in lung transplant recipients who discontinued valganciclovir early due to myelosuppression and in seronegative transplant recipients receiving a CMV-seropositive graft. 24 Antiviral prophylaxis may also be used to prevent CMV disease in SOT recipients; however, its use may be limited due to the development of resistance associated with choice of antiviral drug for prophylaxis, dosing, and serious toxicities.15,25 Another concern for using prophylaxis in CMV infection is the emergence of CMV viremia, 26 which has been shown to be associated with overall survival. 27 CMV infection may fail to respond to therapy, with or without demonstrating genotypic mutation(s) known to be associated with resistance to these therapies. 28 Treatment of such refractory with or without resistance (R+/R-) PT-CMV infection is a major challenge to clinicians, due to the limited number of available approved drug therapies, 29 less-than-optimal efficacy,29,30 associated serious toxicities,22,31 and the emergence of cross-resistance. 16
More recently, novel antiviral therapies with improved safety profiles have come to the forefront for the prevention and treatment of refractory PT-CMV infections. These include maribavir, a benzimidazole riboside that inhibits CMV-DNA replication, 32 and prophylaxis with letermovir, an antiviral agent that inhibits CMV replication. 33 However, real-world data on their use especially in Central and Eastern European countries are limited. Few real-world studies have investigated the prevalence and treatment practices for refractory R+/R- PT-CMV infection. Robust real-world evidence is required to understand the typical treatment pathways and unmet needs of transplant recipients with refractory R+/R- PT-CMV infection in the region. This study aimed to estimate the prevalence of refractory CMV infection in transplant recipients over the past 12 months in Central and Eastern Europe, as reported by physicians treating these patients. Additionally, current treatment modalities, challenges, and unmet needs for managing patients with refractory R+/R- PT-CMV infection in Central and Eastern Europe were assessed.
2. Materials and methods
2.1. Study design and data source
A cross-sectional study conducted from June 2023 to October 2023 surveyed physicians responsible for PT care of adult SOT and HSCT recipients across Central and Eastern Europe (Bosnia and Herzegovina [BIH], Bulgaria [BGR], Croatia [HRV], Estonia [EST], Hungary [HUN], Latvia [LVA], Lithuania [LTU], Poland [POL], Romania [ROU], Serbia [SRB], Slovenia [SVN], and Switzerland [CHE]). Data were collected via an anonymous, one-time, self-reported, and self-completed online structured questionnaire by Adelphi Real World (ARW) through two fieldwork agencies.
The primary objective of this study was to estimate the prevalence of CMV infection, with a focus on refractory R+/R- PT-CMV infection, in patients receiving a transplant in the past 12 months in Central and Eastern Europe, based on reports by physicians managing the treatment. For the purposes of this study, the term refractory CMV infection was defined as follows: “CMV viremia that fails to decrease when the patient is appropriately dosed and delivered antiviral therapy, based on local practice. Patients may be considered refractory both in the presence or absence of known genetic mutations to the available antiviral agents.” The secondary objectives were to describe physician-reported treatment pathways and effectiveness in transplant recipients with refractory R+/R- PT-CMV infection and identify challenges and unmet needs in managing these patients.
2.2. Ethical considerations
Physicians provided informed consent to participate in the survey, and those who completed the survey were compensated with a fair market value in alignment with local compliance. The study was conducted in full conformance with the European Pharmaceutical Market Research Association (EphMRA) guidelines, 34 the Guidelines for Good Publication Practice (GPP) published by the International Society for Pharmacoepidemiology (ISPE), 35 and the laws and regulations of the country in which the research was conducted. The local regulatory authority requirements were met before the start of the study. The methodological review was conducted by a centralized Institutional Review Board (IRB)/Ethics Committee (EC), along with confirmation that there was no need for an ethical review, as the study did not involve the collection of patient-level medical data. The reporting of this study was guided by the standards of the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) Statement. 36
2.3. Study population
We enrolled physicians, including infectious disease specialists, cardiologists, pulmonologists, gastroenterologists/hepatologists, nephrologists, and hematologists, who spent at least 50% of their professional time on PT recipient care, had a minimum of 5 years of experience in treating transplant recipients, and were responsible for the treatment and management of a prespecified minimum number of transplant recipients (Supplementary Table 1). No transplant recipients were included in this study. No attempts were made to provide regional representation within each country because of the limited number of treatment centers from which physicians were recruited, and convenience sampling was employed.
2.4. Questionnaire design
The questionnaire, designed to capture physicians’ attitudes and experiences with PT-CMV infection, included the following sections: healthcare professional screening, demographics, current caseload, typical treatment modalities, unmet needs, and challenges. Details of the survey questions are presented in Supplementary Table 2. The survey required up to 1 h to complete and was translated into the local language(s) of each country. To ensure maximum data quality, standardized instructions for survey completion were included within the survey, standardized question formats were used, and quality checks were built into the programming code. The questions included categorical single-choice, categorical multiple-choice, and continuous numerical questions. The survey had to have a minimum of 50% of responses from a respondent to be included.
2.5. Statistical analyses
No specific hypotheses were tested in this study, and no patient-reported outcomes were collected. All analyses were descriptive in nature. Categorical variables were presented as the number of observations and percentages within each category and the number of missing observations. Continuous variables were presented as the number of observations, mean (standard deviation [SD]), median (minimum and maximum; interquartile range), and number of missing observations. The final data were stratified based on country, physician specialties and transplant type (HSCT or SOT). Statistical analyses were performed by ARW using IBM Survey Reporter, version 7.5.
3. Results
3.1. Survey respondents and their patient characteristics
A total of 164 physicians from 12 countries completed the survey. Most physicians were recruited from POL (15.2%), CHE (14.0%), or ROU (12.2%) and were nephrologists (23.8%) and hematologists (22.6%) (Supplementary Table 3). Overall, 51.8% of the physicians selected teaching hospitals as their primary setting for treating transplant recipients with PT-CMV infection (Supplementary Table 3).
Physicians also reported the demographics and comorbidities of their transplant recipients (Supplementary Table 4). On average, physician responses indicated that a higher proportion of their current transplant recipients were aged 41–55 years (34.2%), were male (56.8%), and had received immunosuppressive therapy (85.5%). Across transplant types, almost all SOT recipients received immunosuppressive therapy (median range across specialties: 95.0%–100.0%) compared with a median of 80% of HSCT recipients. Cardiovascular disease (mean: 37.3%), bacterial infection (mean: 28.5%), kidney disease (mean: 27.9%), and diabetes (mean: 19.4%) were the most commonly reported comorbidities among the transplant recipients.
3.2. Physician-reported prevalence of CMV infection among patients who received a transplant in the past 12 months
Across all countries and transplant types, physicians (n=90) estimated that 26.4% of patients who received a transplant in the past 12 months developed a PT-CMV infection (Figure 1). The physician-estimated incidence of PT-CMV infection in patients who received a transplant in the past 12 months varied across transplant types, ranged from 10.4% to 26.6% for SOT and 37.0% for HSCT recipients. Among countries, the estimated proportions ranged from 12.0% in HRV to 63.2% in LTU. Of the 715 reported patients with PT-CMV infection, an estimated 41.1% were symptomatic and 58.0% were asymptomatic (Table 1). A higher proportion of patients who received a liver/pancreas/intestine transplant were symptomatic (55.1%) than asymptomatic (44.1%) (Table 1). A higher proportion of patients in BGR, HUN, POL, ROU, SRB, and CHE were reported to be symptomatic than asymptomatic (Supplementary Table 5). Physician-reported prevalence of PT-CMV infection by country and transplant type. BIH, Bosnia and Herzegovina; BGR, Bulgaria; CHE, Switzerland; EST, Estonia; HRV, Croatia; HSCT, hematopoietic stem cell transplantation; HUN, Hungary; LTU, Lithuania; POL, Poland; PT-CMV, posttransplant cytomegalovirus infection; ROU, Romania; SRB, Serbia; SVN, Slovenia. Physician-reported prevalence of PT-CMV infection subtypes by transplant type. AE, adverse event; CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; PT-CMV, posttransplant cytomegalovirus; R+/R-, with or without resistance. aSymptomatic CMV is defined as an episode wherein there is “tissue invasive or end organ disease” or “CMV syndrome” at any time. bAsymptomatic CMV is defined as an episode considered by the treating physician as “viremia only”. cTreatment intolerance is defined as patient inability to tolerate antiviral therapy due to AEs (e.g., gastrointestinal toxicity, myelosuppression) OR considered at risk of experiencing a serious AE to currently available antiviral agents. dRecurrent infection is defined as a new CMV infection in a patient with previous evidence of CMV infection within 6 months of treatment discontinuation. eRefractory R+/R- CMV infection is defined as CMV viremia that fails to decrease when the patient is appropriately dosed and delivered antiviral therapy, based on local practice. Patients may be considered refractory to available antiviral agents, both in the presence and absence of known genetic mutations.
Overall, an estimated 12.9% of patients who had received a transplant in the past 12 months and developed PT-CMV infection were estimated to have refractory R+/R-infection, ranging from 17.9% in kidney transplant recipients to 8.5% in both liver/pancreas/intestine and heart transplant recipients (Table 1). The estimated proportion of patients with refractory R+/R- PT-CMV infection also varied between countries, ranging from 5.6% in SVN to 27.5% in BGR (Supplementary Table 5). The prevalence of refractory R+/R- PT-CMV infection was 16.0% and 10.8% among symptomatic and asymptomatic patients with PT-CMV infection, respectively. Overall, among patients with PT-CMV infection, physicians reported recurrent infection in 35.8% and treatment intolerance in 21.0% (Table 1).
3.3. Physician-reported typical treatment pathways and treatment attributes
3.3.1. Treatment of patients with PT-CMV infection
Most surveyed physicians (142/164; 86.6%) indicated that they were treating at least one patient with PT-CMV infection at the time of the survey. Physicians estimated that a mean (±SD) of 66.5%±33.4% of their current patients with PT-CMV infection were receiving first-line treatment, 16.5%±23.2% were receiving second-line treatment, and 4.0%±9.1% were receiving third- or later line of treatment at the time of the survey completion (Supplementary Figure 1).
During the survey period, the most commonly reported first-line treatment was oral valganciclovir (mean±SD, 38.1%±38.9%), followed by IV ganciclovir (29.3%±32.7%) and oral ganciclovir (24.9%±34.3%). The most commonly reported second-line treatments were foscarnet (28.5%±35.8%) and IV ganciclovir (23.9%±30.7%), whereas foscarnet (21.4%±27.5%) and cidofovir (15.5%±24.0%) were the most frequently prescribed third-line treatments (Supplementary Table 6). Other relatively newer anti-CMV therapies were also prescribed as second- and third-line treatments. An estimated 10.0%±23.7% and 7.8%±11.2% of patients were prescribed letermovir prophylaxis as second- and third-line agent, respectively, and 4.7%±9.1% and 13.8%±21.9% were prescribed maribavir as second- and third-line treatments, respectively. A similar trend was observed across physician specialties (Supplementary Table 6) and countries (Supplementary Table 7).
Overall, physicians treating at least one patient with PT-CMV infection estimated that a mean (±SD) of 13.0%±27.4% of patients did not receive any PT-CMV treatment at the time of survey completion. Physicians most commonly attributed this lack of treatment to tolerability issues (55.6%), patient preference (28.9%), and patient’s insurance not covering the treatment prescribed and the absence of other suitable options (13.3%) (Supplementary Table 8).
3.3.2. Treatment of patients with refractory R+/R- PT-CMV infection
Overall, 32.4% (46/142) of physicians reported that they were currently treating at least one patient with refractory R+/R- PT-CMV infection. Among the patients with refractory R+/R- PT-CMV infection, physicians reported that most (mean±SD: 22.1%±28.5%) were prescribed oral valganciclovir, followed by oral ganciclovir (18.8%±29.8%) and foscarnet (17.7%±27.8%) (Supplementary Table 6). Physicians indicated that 7.8%±21.8% of patients with refractory R+/R- PT-CMV infection did not receive any treatment.
3.3.3. Treatment attributes
For the management and treatment of patients with PT-CMV infection, most physicians rated maintenance of CMV viremia clearance (94.5%), good symptom control (94.5%), and lack of renal toxicity (93.9%) as moderately-to-extremely important treatment attributes (Figure 2). Importance of treatment attributes in managing patients with PT-CMV infection. CMV, cytomegalovirus; PT-CMV, posttransplant cytomegalovirus. Sum of percentages may not total 100% due to rounding.
Compared with other available treatments, more physicians indicated that oral valganciclovir had strong-to-complete association with the treatment attributes considered extremely important (maintenance of CMV viremia clearance, 67.7%; good symptom control, 65.2%; and lack of renal toxicity, 52.4%) (Supplementary Figure 2). Approximately more than half of the physicians reported no experience with maribavir and letermovir. However, among physicians with treatment experience, most reported maribavir to have a strong-to-complete association with low incidence of resistance (77.6%, n=59/76), maintenance of CMV viremia clearance (75.6%, n=59/78), good symptom control (73.4%, n=58/79), rapid viremia clearance (70.1%, n=54/77), and lack of renal toxicity (70.1%, n=54/77).
3.4. Challenges and unmet needs with managing patients with refractory R+/R- PT-CMV infection
3.4.1. Overall satisfaction with available treatment options
Overall, 63.4% of physicians indicated some level of satisfaction (21.3% of patients were slightly satisfied, 34.2% were moderately satisfied, and 7.9% were completely satisfied) with the conventional treatments available for refractory R+/R- PT-CMV infection. Compared with other specialties, a relatively higher proportion of pulmonologists (62.5%) and cardiologists (54.2%) reported moderate-to-complete satisfaction with the currently available treatments (Supplementary Figure 3). More physicians reported having moderate-to-complete satisfaction with IV ganciclovir (59.1%) and oral valganciclovir (56.1%) compared with other treatments (Figure 3). Consistent with responses regarding the association with treatment attributes, more than half of the surveyed physicians reported no experience with maribavir (54.9%) refractory R+/R- PT-CMV infection treatment and letermovir for the prophylaxis of PT-CMV infection (50.6%) (Figure 3). However, among physicians who had experience using maribavir (n=74), 45.9% (n=34/74) reported moderate-to-complete satisfaction with the treatment. Overall physician satisfaction with treatments for transplant recipients with PT-CMV infection. IV, intravenous; PT-CMV, posttransplant cytomegalovirus. Sum of percentages may not total 100% due to rounding.
Overall, physicians’ reasons for dissatisfaction with treatments included “limited treatment options” (47.7%), “treatment options are not available at my site” (29.8%), “patients are often resistant to treatments” (28.5%), and “treatment options are limited to certain patient groups” (28.5%) (Supplementary Table 9). A similar trend in results was observed across the specialties (Supplementary Table 9) and countries (Supplementary Table 10).
3.4.2. Treatment goals and barriers for patients with refractory R+/R- PT-CMV infection
Almost half (48.8%) of the physicians selected preventing early death as the most important treatment goal for patients with refractory R+/R- PT-CMV infection. Other important goals to physicians included reducing the likelihood of CMV recurrence (14.0%) and improving the patient’s quality of life (11.0%) (Supplementary Figure 4). Similar trend was observed across the specialties (Supplementary Figure 4) and countries (Supplementary Table 11). However, only 11.0% of physicians were completely satisfied with the ability of current treatments to prevent early death (Supplementary Figure 5).
On being asked to rate factors affecting their ability to provide optimum treatment to their patients, physicians most frequently indicated that the unavailability of adequate treatment (43.3%), lack of healthcare reimbursement options (35.4%), difficulties faced by transplant recipients in traveling to receive treatment (29.9%), and limited access to outpatient services (29.3%) had a major effect on the treatments they could prescribe (Supplementary Figure 6).
4. Discussion
In this real-world evidence study, surveyed physicians in 12 Central and Eastern European countries reported that 26.4% of their patients had PT-CMV infection in the past 12 months, and approximately 13% of them were estimated to have refractory R+/R- PT-CMV infection, with the rates varying with symptom status. When managing patients with PT-CMV infection, most physicians considered the maintenance of CMV viremia clearance, good symptom control and lack of renal toxicity as the three most important treatment attributes. Less than half of the physicians reported moderate-to-complete satisfaction with the treatment options for transplant recipients with PT-CMV infection. However, more than half of the physicians reported having no experience with newer anti-CMV options, such as maribavir for refractory R+/R- PT-CMV infection treatment and letermovir for the prophylaxis of PT-CMV infection. Overall, physicians considered limited treatment options, inadequate healthcare reimbursement, and inaccessible healthcare services as major barriers to providing optimum treatment to patients with refractory R+/R- PT-CMV infection.
The incidence of PT-CMV infection varies based on factors such as serological match between donor and recipient, use of prophylaxis treatment and/or immunosuppressive drugs, and other risk factors of recipients, 4 making comparisons of prevalence estimates challenging. In Germany, a retrospective study based on a claims dataset found that between 2014 and 2019, 29.2% of allogeneic HSCT recipients and 16.8% of SOT recipients were diagnosed with CMV infection within a year of transplantation. 37 In France, single-institution data from 208 adult transplant recipients between 2008 and 2013 showed that CMV disease occurred in 34.0% of patients in the first 12 months following allogeneic HSCT. 38 In Spain, 20.0% of heart transplant recipients developed CMV infection. 39
The incidence of refractory CMV infection has not been well documented in the literature. Studies have shown that refractory CMV infection incidence varies from 8.5% to 50% in allogeneic HSCT recipients40–42 Such variation in the incidence of refractory PT-CMV infection is likely because of inconsistent definitions for resistant/refractory CMV in clinical practice as well as clinical trials,28,43 which makes comparison with findings from the current study challenging.
A wide variation was also observed in the estimated proportion of patients with refractory R+/R- PT-CMV infection among Central and Eastern European countries in the current study, with prevalence ranging from 5.6% in Slovenia to 27.5% in Bulgaria. These variations across countries may reflect differences in CMV screening protocols, viral load monitoring practices, thresholds for defining viral load, diagnostic tool availability, local clinical approaches, and national guidelines. While this survey aimed to capture insights into current prevalence and management trends of PT-CMV from the physician’s perspective, the findings highlight a potential need for more standardized care across the region, tailored to its specific needs and challenges.
In this study, physicians reported that the most common first-line treatment for PT-CMV infection was oral valganciclovir (38.1%), which is in line with other studies reporting valganciclovir as the primary treatment for CMV infection and disease. 23 Oral valganciclovir has emerged as the preferred antiviral for PT-CMV infection owing to convenient dosing schedule and higher bioavailability compared with oral ganciclovir.44,45 However, treatment options for refractory CMV infection are limited due to serious toxicity concerns and intolerance to conventional anti-CMV agents or complications associated with the transplant. 43 Among patients with refractory R+/R- PT-CMV infection in this study, oral valganciclovir was reported to be the most common treatment (22.1%), with 7.8% of patients not receiving any treatment. Overall, less than half of the surveyed physicians reported moderate-to-complete satisfaction with the treatment of transplant recipients with refractory R+/R- PT-CMV infection, with physicians indicating limited treatment options and unavailability of treatments at the treatment site as the major reasons for dissatisfaction. Access to and availability of suitable treatments with a better tolerability profile are major unmet needs for the management of patients with refractory R+/R- PT-CMV infection in the Central and Eastern European countries surveyed. Maribavir has emerged as a viable treatment option for refractory R+/R-PT-CMV infection. Maribavir exhibits multimodal anti-CMV activity via the inhibition of UL97 protein kinase and its natural substrates, leading to the inhibition of CMV-DNA replication, encapsidation, and nuclear egress of viral capsids.32,46,47 Results from a Phase III, open-label study in HSCT and SOT recipients reported that maribavir 400 mg twice daily was superior to investigator-assigned therapy (valganciclovir/ganciclovir, foscarnet, or cidofovir) for CMV viremia clearance and viremia clearance plus symptom control maintained posttherapy in transplant recipients with refractory R+/R- CMV infection. 47 Moreover, several studies have shown maribavir as a cost-effective option compared with other antiviral therapies in patients with refractory R+/R- PT-CMV infection.48,49 Maribavir is approved by Food and Drug Administration (FDA) 50 and European Medicines Agency (EMA) 51 for the treatment PT-CMV infection that is refractory to treatment with ganciclovir, valganciclovir, cidofovir or foscarnet. Similarly, prophylaxis with letermovir resulted in a significantly lower risk of clinically significant CMV infection than with placebo after allogeneic HSCT, with mainly low-grade adverse events. 33 Letermovir for prophylaxis of CMV infection has received market authorization by the FDA 52 and EMA 53 for CMV-seropositive adults who underwent HSCT. The EMA has also indicated letermovir for prophylaxis in CMV-seronegative adults who have received a kidney transplant from a CMV-seropositive donor. 37 Notably, there are conflicting reports about the potential association of letermovir prophylaxis with an increase in Epstein–Barr virus reactivation and risk of posttransplant lymphoproliferative disorders after HSCT54–59; however, this has not been assessed in patients in Central and Eastern European countries.
In this study, more than half of physicians reported no experience with maribavir and letermovir. The limited use of newer antiviral therapies could be attributed to the extended interval between EMA authorization and receipt of reimbursement approval, which may range from 128 days in Germany to 1351 days in Malta for innovative treatments in the European Union and European Economic Area countries, 60 and the potentially high cost of medication. Moreover, since maribavir was recently launched (November 2022) at the time of the study, there was limited post-launch real-world evidence, likely further contributing to the lack of awareness among physicians. 3 Notably, in this study, physicians indicated the lack of adequate treatments and reimbursements options as major barriers to achieving optimum treatment outcomes for refractory R+/R- PT-CMV infection. Increasing the access to and availability of newly approved anti-CMV drugs by facilitating reimbursement processes and introducing targeted training/educational programs to increase awareness can contribute to the improvement of patient outcomes.
This study has some limitations. Recall bias may have affected the physicians’ ability to accurately recollect previous workloads or experiences. While the survey questionnaire was designed to carefully articulate the research questions and avoid ambiguities to minimize recall bias, our findings may be an over- or underestimation of the true prevalence of refractory R+/R- PT-CMV infection. The sample size of the survey was limited; therefore, any country- or specialty-level subgroup analysis should be interpreted with caution due to high heterogeneity in the data. A nonstandard physician-driven definition of refractory CMV was used to overcome local/region-specific differences in how refractory CMV was defined. However, this may have led to an overestimation of the prevalence of refractory CMV. To meet the primary objective of this study, physicians were not required to treat a minimum number of transplant recipients with refractory R+/R-PT -CMV infection, as this may have biased epidemiological calculations. Therefore, physicians may have answered questions about the secondary objectives of treatment pathways and unmet needs in refractory R+/R- PT-CMV infection, without direct experience in treating these patients. Objective data on monitoring frequency, viral load thresholds for therapy initiation, and immunosuppression intensities across sites were not recorded; these missing variables may have provided insight into observed prevalence and treatment patterns across countries. Moreover, convenience sampling was employed to recruit transplant physicians with specific experience criteria; this limited the generalizability of the results, as these findings may not be representative of the larger population due to selection biases and potential overrepresentation. Indeed, although quotas were set to ensure that all physician specialties were included in the study, there was an overrepresentation of pulmonologists, cardiologists, and gastroenterologists/hepatologists compared with global expectations, which led to an overrepresentation of their patient types in the analyses. This may have affected the whole sample mean estimate of the proportion of patients with PT-CMV infection and those with refractory R+/R- PT-CMV infection, which was mitigated by the use of “per-transplant type” calculations when estimating the numbers of patients with PT-CMV infection and those with refractory R+/R- PT-CMV infection. Despite these limitations, the findings from this study are relevant, as it is the first such study to provide real-world data regarding the epidemiology of PT-CMV infection and insights into current unmet needs for the management of patients with PT-CMV infection in Central and Eastern European countries. Moreover, this survey sampled a cross-section of physicians providing PT care across different specialties, countries, and sites of practice.
5. Conclusions
Accurate epidemiological insights into prevalence, routine clinical approaches, and physician viewpoints are essential for deepening scientific understanding of the unmet needs in managing refractory R+/R-post-transplant CMV infections across Central and Eastern Europe. This study provides real-world data from this region, helping to close existing knowledge gaps on treatment patterns and clinical challenges faced by healthcare providers. The study emphasizes the urgency of enhancing physician education and awareness, particularly regarding newly approved antiviral agents—such as maribavir for treating refractory CMV and letermovir for its prophylactic use. These findings may empower clinicians and healthcare stakeholders to make better-informed therapeutic decisions and support reimbursement efforts, ultimately improving treatment access and patient outcomes.
Supplemental material
Supplemental material - Epidemiology and clinical management of cytomegalovirus infection in transplant recipients in Central and Eastern Europe – a physician survey
Supplemental material Epidemiology and clinical management of cytomegalovirus infection in transplant recipients in Central and Eastern Europe – a physician survey by Alicja Dębska-Ślizień, Milena Todorović Balint, Radovan Vrhovac, Aleksandar Biljić Erski and Tina Roblek in Antiviral Therapy.
Footnotes
Acknowledgments
Medical writing support for the development of this manuscript was provided by Neha Shrestha, PhD, of Cactus Life Sciences (part of Cactus Communications) and funded by Takeda Pharma OÜ.
Ethical considerations
Physicians provided informed consent to participate in the survey, and those who completed the survey were compensated with a fair market value in alignment with local compliance. The study was conducted in full conformance with the European Pharmaceutical Market Research Association (EphMRA) guidelines, the Guidelines for Good Publication Practice (GPP) published by the International Society for Pharmacoepidemiology (ISPE), and the laws and regulations of the country in which the research was conducted. The local regulatory authority requirements were met before the start of the study. The methodological review was conducted by a centralized Institutional Review Board (IRB)/Ethics Committee (EC), along with confirmation that there was no need for an ethical review, as the study did not involve the collection of patient-level medical data.
Consent to participate
All the physicians participating in the survey have agreed to provide their personal information electronically as part of the survey questionnaire. Consent was obtained by clearly communicating the purpose of the study, ensuring comprehension of the information provided, and confirming voluntary participation. Participants provided written informed consent to conduct the study and publish the study.
Author contributions
All the authors were involved in drafting and critically revising the manuscript for important intellectual content. All authors have approved the final version of the manuscript for publication. Study concept, design, and protocol development were performed by ADS, TR, ABE, MTB, and RV. Data acquisition was performed by TR and ABE with support from Adelphi Real World (ARW). Data analysis and interpretation were performed by ADS, TR, ABE, MTB, and RV with support from ARW. Part of the data in the manuscript was previously presented at the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation in Glasgow, United Kingdom (April 14–17, 2024).
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Takeda Pharma OÜ.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Alicja Dębska-Ślizień is a consultant, speaker, advisory board member, and investigator in clinical trials for AstraZeneca, Bayer, Astellas, Takeda, GSK, Boehringer Ingelheim, and Chiesi. Milena Todorović Balint received speaker fees from MSD, Roche, Takeda, Astellas, Novartis, and Pfizer and participated in advisory committees of MSD, Roche, Takeda, Astellas, Novartis, and Pfizer. Radovan Vrhovac received speaker fees from Takeda, AbbVie, Astellas, Pfizer, MSD, Novartis, Zentiva, and Medis Adria and participated in the advisory committees of Takeda, AbbVie, Servier, and Swixx. Radovan Vrhovac, Milena Todorović Balint, and Alicja Dębska-Ślizień received funding for protocol development and review of this study from Takeda. Aleksandar Biljić Erski and Tina Roblek are employees of Takeda.
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due to confidentiality agreements with the study sponsor. However, they are available from the study sponsor upon reasonable request. Requests for access should be directed to the corresponding author.
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