Refractory Cytomegalovirus Infection Research Articles

Cost‐effectiveness of maribavir versus conventional antiviral therapies for post‐transplant refractory cytomegalovirus infection with or without genotypic resistance: A US perspective

AbstractThis study evaluated the cost‐effectiveness of maribavir versus investigator‐assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post‐transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two‐stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real‐world multinational observational studies, and published literature. Stage 1 (0–78 weeks) comprised clinically significant CMV (csCMV), non‐clinically significant CMV (n‐csCMV), and dead states; stage 2 (78 weeks–lifetime) comprised alive and dead states. Total costs (2022 USD) and quality‐adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost‐effectiveness ratio was calculated to determine cost‐effectiveness against a willingness‐to‐pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost‐saving and more cost‐effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost‐saving. Maribavir‐treated patients spent more time without CMV compared with IAT‐treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: −$42 970.80). Compared with IAT, maribavir was more cost‐effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision‐makers on the most effective use of their resources for post‐transplant refractory CMV treatment.

A time trade-off study to determine health-state utilities of transplant recipients with refractory cytomegalovirus infection with or without resistance

BackgroundHealth-state utility values (HSUVs) for post-transplant refractory cytomegalovirus (CMV) infection (with or without resistance [R/R]) were determined using a time trade-off (TTO) survey completed by 1,020 members of the UK general public.MethodsExisting literature and qualitative interviews with clinicians experienced in treating R/R CMV were used to develop initial draft vignettes of health states. The vignettes were refined to describe three clinical states of R/R CMV: clinically significant and symptomatic (CS-symptomatic CMV); clinically significant and asymptomatic (CS-asymptomatic CMV); and non-clinically significant (non-CS CMV). Each clinical state was valued independently and combined with three events of interest: graft-versus-host disease; kidney graft loss; and lung graft loss to generate twelve vignettes. The final vignettes were evaluated by a sample of the UK general public using an online TTO survey. Exclusion criteria were applied to the final data to ensure that responses included in the analysis met pre-defined quality control criteria.ResultsOverall, 738 participants met the inclusion criteria and were included in the analysis. The sample was representative of the UK general population in terms of age and sex. Non-CS CMV had the highest mean HSUV (95% confidence interval) (0.815 [0.791, 0.839]), followed by CS-asymptomatic CMV (0.635 [0.602, 0.669]), and CS-symptomatic CMV (0.443 [0.404, 0.482]). CS-symptomatic CMV with lung graft loss had the lowest mean HSUV (0.289), with none of the health states considered on average worse than dead.ConclusionsPost transplant R/R CMV has substantial impact on the health-related quality of life of patients. The utility values obtained in this study may be used to support economic evaluations of therapies for R/R CMV infection.

Refractory cytomegalovirus infections in Chinese patients receiving allogeneic hematopoietic cell transplantation: a review of the literature.

In the absence of prophylactic therapy, cytomegalovirus (CMV) viremia is a common complication following allogeneic hematopoietic cell transplantation (allo-HCT) and represents a significant cause of morbidity and mortality. Approximately 25% of allo-HCT happen in China, where the development and refinement of the 'Beijing protocol' has enabled frequent and increasing use of haploidentical donors. However, refractory CMV infection (an increase by >1 log10 in blood or serum CMV DNA levels after at least 2 weeks of an appropriately dosed anti-CMV medication) is more common among patients with haploidentical donors than with other donor types and has no established standard of care. Here, we review the literature regarding refractory CMV infection following allo-HCT in China.

Adoptive Therapy with Cytomegalovirus-Specific Cytotoxic T Lymphocytes for Refractory Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Cytomegalovirus (CMV) infection remains a common complication in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The rates of refractory CMV infection are reported in allo-HSCT recipients ranging from 19.0% to 50.6%. Patients with refractory CMV infection have a higher incidence of CMV disease and non-relapse mortality than those without refractory CMV infection, and the antiviral drug has limited efficacy. In this study, we retrospectively compared the efficacy and safety of donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in patients with refractory CMV infection and disease after allo-HSCT in the context of the new definitions. Methods: This study examined all consecutive patients who received CMV-CTL therapy for refractory CMV infection and disease after allo-HSCT at our center from January 2017 to September 2021. Refractory CMV infection referred to refractory CMV DNAemia, which was defined by a >1 log 10 increase in CMV DNA levels in blood after at least 2 weeks of appropriately dosed antiviral therapy. Refractory CMV disease referred to refractory CMV end-organ disease, which was defined by a worsening in signs and symptoms or progression into end-organ disease after at least 2 weeks of appropriately dosed antiviral therapy. This study mainly focused on the therapeutic response, overall survival (OS) and safety evaluation. Complete response (CR) was defined as undetectable CMV DNA by quantitative PCR in two consecutive tests coupled with the resolution of clinical signs and symptoms. Results:A total of 53 patients who received CMV-CTL therapy for refractory CMV DNAemia and disease after allo-HSCT were enrolled in this study, including 40 in the donor CMV-CTL group and 13 in the third-party CMV-CTL group. Of the 40 patients with donor CMV-CTLs, 20 were refractory CMV DNAemia, and 20 were refractory CMV end-organ diseases. Of the 13 patients with third-party CMV-CTLs, 7 were refractory CMV DNAemia, and 6 had refractory CMV end-organ diseases. Within 6 weeks of treatment, 26 (65.0%) patients and 9 (69.2%) patients achieved CR in the donor and third-party groups (P=1.00). The CR rates at 6 weeks after the first CMV-CTL infusion were 65.0% (95% CI 49.5%-77.9%) in the donor group and 69.2% (95% CI 42.4%-87.3%) in the third-party group. At the date of statistical analysis (September 30, 2022), 16 patients died in the donor CMV-CTL group and 6 died in the third-party CMV-CTL group. Causes of death were relapse of the primary diseases (n=3; 3 in the donor group), CMV diseases (n=5; 4 in the donor group and 1 in the third-party group), mixed infections (n=9; 6 in the donor group and 3 in the third-party group), bacterial infection (n=4; 2 in each group), and fungal infection (n=1; 1 in the donor group). The OS at 2 year was 59.6% (95%CI 46.1%-77.1%) in the donor group and 53.8% (95% CI 32.6%-89.1%) in the third-party group (P=0.860). Conclusion:This study contributes important information regarding the comparable antiviral efficacy and safety of donor or third-party CMV-CTLs for refractory CMV infection and disease after allo-HSCT.

Updates in Cytomegalovirus Prevention and Treatment in Solid Organ Transplantation.

The authors summarize recent updates in the prevention and management of cytomegalovirus (CMV) in solid organ transplant (SOT) recipients with a focus on CMV seronegative recipients of organs from seropositive donors (CMV D+/R-) who are at highest risk of CMV infection and disease. They discuss advantages of preemptive therapy for CMV disease prevention in CMV D+/R- liver transplant recipients, letermovir for CMV prophylaxis, and updates in the development of monoclonal antibodies and vaccines as immune-based preventative strategies. They review the roles of maribavir and virus-specific Tcells for management of resistant or refractory CMV infection in SOT recipients.

Cytomegalovirus Infection after Allogeneic Hematopoietic Cell Transplantation under 100-Day Letermovir Prophylaxis: A Real-World 1-Year Follow-Up Study.

The prevention and management of cytomegalovirus (CMV) reactivation is important to improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The aim of this study was to analyze real-world data regarding the incidence and characteristics of CMV infections until 1 year after allo-HCT under 100-day letermovir prophylaxis. A single-center retrospective study was conducted between November 2020 and October 2021. During the study period, 358 patients underwent allo-HCT, 306 of whom received letermovir prophylaxis. Cumulative incidence of clinically significant CMV infection (CS-CMVi) was 11.4%, 31.7%, and 36.9% at 14 weeks, 24 weeks, and 1 year post-HCT, respectively. Through multivariate analysis, the risk of CS-CMVi increased with graft-versus-host disease (GVHD) ≥ grade 2 (adjusted odds ratio 3.640 [2.036-6.510]; p < 0.001). One-year non-relapse mortality was significantly higher in letermovir breakthrough CS-CMVi patients than those with subclinical CMV reactivation who continued receiving letermovir (p = 0.002). There were 18 (15.9%) refractory CMV infection cases in this study population. In summary, letermovir prophylaxis is effective at preventing CS-CMVi until day 100, which increased after the cessation of letermovir. GVHD is still a significant risk factor in the era of letermovir prophylaxis. Further research is needed to establish individualized management strategies, especially in patients with significant GVHD or letermovir breakthrough CS-CMVi.

Retrospective chart review of transplant recipients with cytomegalovirus infection who received maribavir in the Phase 3 SOLSTICE trial: Data at 52weeks post-maribavir treatment initiation.

Cytomegalovirus (CMV) infection is a frequent complication in haematopoietic cell/solid organ transplant (HCT/SOT) recipients. Previous studies report all-cause mortality rates of 31% and 50% in HCT/SOT recipients post-treatment initiation with conventional anti-CMV therapies for refractory or resistant CMV. This was a multi-country, retrospective medical chart review study of HCT/SOT recipients with refractory CMV infection with or without resistance (R/R) who were randomized to the maribavir arm in the open-label Phase 3 SOLSTICE trial. Patients came from 21 SOLSTICE sites across 6 countries; each site randomized ≥3 patients to the maribavir arm. Patients were followed for 52weeks (SOLSTICE trial period: 20weeks; follow-up chart review period: 32weeks). The primary outcomes were mortality and graft status. Of 234 patients who were randomized and received maribavir in SOLSTICE, chart abstraction was completed for all 109 patients enrolled across 21 trial sites (SOT, 68/142; HCT, 41/92). At 52weeks, overall mortality was 15.6% (17/109) and survival probability was 0.84. Among SOT recipients, survival probability was 0.96, and 3 (4.4%) deaths occurred during the chart review period. For the HCT recipients, survival probability was 0.65 with 14 (34.1%) deaths; 8 occurred during SOLSTICE and 6 during the chart review period. No new graft loss or re-transplantation occurred during the chart review period. Overall mortality at 52weeks post-maribavir treatment initiation in this sub-cohort of patients from the SOLSTICE trial was lower than that previously reported for similar populations treated with conventional therapies for R/R cytomegalovirus infection.

CMV hyperimmune globulin as salvage therapy for recurrent or refractory CMV infection in children undergoing hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) is a major cause of allogeneic hematopoietic stem cell transplant (HSCT)-related morbidity and mortality. Treatment failure continues to be a major issue in patients with CMV infection due to both drug resistance and intolerance. This single-center brief retrospective analysis of a case series aims to investigate the safety and efficacy of CMV-hyperimmune globulin as salvage therapy for CMV infection in children undergoing HSCT. Fifteen pediatric patients received human CMV-specific immunoglobulin (CMVIG) between July 2018 and December 2021 as a salvage therapy for refractory or recurrent CMV infection. At the time of CMVIG prescription, eight children presented with recurrent CMV infection and seven with refractory CMV infection. The overall response rate was 67% at 50 days from the CMVIG administration [95% confidence interval (CI): 44-88]. Overall survival (OS) from CMVIG administration at 100 days was 87% (95% CI: 56-96), and OS from HSCT at 1 year was 80% (95% CI: 50-93). Four patients died, three unrelated to CMV infection and one due to CMV pneumonia. CMVIG as salvage therapy was well tolerated, and no infusion-related adverse events were observed.

Refractory CMV infection in post-transplant phase: epidemiological framing in the Italian context, current patient management and unmet needs

Background: Cytomegalovirus (CMV) infection usually occurs asymptomatically but can represent an important cause of morbidity and mortality in patients with compromised immune system such as transplant patients. Infection may not respond to standard therapies leading to refractoriness (with or without resistance) which jeopardizes transplant successful outcome. Objective: Since refractoriness represents a critical point, a project has been conducted to verify the epidemiology in the Italian context and to convey the current patients’ unmet medical needs. Methods: The project included: literature analysis, expert interviews and results’ validation through expert opinion. Based on literature data, a questionnaire was built and submitted to 8 experts with proven experience in the management of post-transplant CMV infection. Topics included epidemiology, patient management, unmet needs and future perspective. Outcomes were validated by 3 additional national experts in solid organ transplantation, hematopoietic stem cell transplantation and infectious diseases. Results: Epidemiological rates from literature applied to current transplantation numbers in Italy estimate approximately 109 adults and 8 children with refractory post-transplant CMV infection in 2021. If valganciclovir/ganciclovir are ineffective, foscarnet is predominantly used. When foscarnet fails, patients have no therapeutic alternatives. Despite being a minority, this represents a high medical need. Therefore, the introduction of new therapeutic options with a better efficacy/safety profile would lead to a significant improvement in refractory CMV infection management. Conclusion: Although refractory infections represent a minority, they are the most critical issue that can occur in post-transplant patients resulting in a high unmet need due to the lack of specific treatment options and the toxicity of current treatments used.

Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection.

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versus 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group.

Clinical Study of Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

To explore the risk factors of cytomegalovirus (CMV) and refractory CMV infection (RCI) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their influences on survival. A total of 246 patients who received allo-HSCT from 2015 to 2020 were divided into CMV group (n=67) and non-CMV group (n=179) according to whether they had CMV infection. Patients with CMV infection were further divided into RCI group (n=18) and non-RCI group (n=49) according to whether they had RCI. The risk factors of CMV infection and RCI were analyzed, and the diagnostic significance of Logistics regression model was verified by ROC curve. The differences of overall survival (OS) and progression-free survival (PFS) between groups and the risk factors affecting OS were analyzed. For patients with CMV infection, the median time of the first CMV infection was 48(7-183) days after allo-HSCT, and the median duration was 21 (7-158) days. Older age, EB viremia and gradeⅡ-Ⅳacute graft-versus-host disease (aGVHD) significantly increased the risk of CMV infection (P=0.032, <0.001 and 0.037, respectively). Risk factors for RCI were EB viremia and the peak value of CMV-DNA at diagnosis≥1×104 copies/ml (P=0.039 and 0.006, respectively). White blood cell (WBC)≥4×109/L at 14 days after transplantation was a protective factor for CMV infection and RCI (P=0.013 and 0.014, respectively). The OS rate in CMV group was significantly lower than that in non-CMV group (P=0.033), and also significantly lower in RCI group than that in non-RCI group (P=0.043). Hematopoietic reconstruction was a favorable factor for OS (P<0.001), whereas CMV-DNA≥1.0×104 copies/ml within 60 days after transplantation was a risk factor for OS (P=0.005). The late recovery of WBC and the combination of EB viremia after transplantation are common risk factors for CMV infection and RCI. CMV-DNA load of 1×104 copies/ml is an important threshold, higher than which is associated with higher RCI and lower OS risk.

Analysis of risk factors and prognosis of cytomegalovirus infection post umbilical cord blood stem cell transplantation in children with primary immunodeficiency diseases

Objective: To investigate the risk factors and outcomes of cytomegalovirus (CMV) infection post umbilical cord blood stem cell transplantation (UCBT) in children with primary immunodeficiency diseases (PID). Methods: Clinical data of 143 PID children who received UCBT in the Children's Hospital of Fudan University from January 2015 to June 2020 were collected retrospectively. CMV-DNA in the plasma was surveilled once or twice a week within 100 days post-UCBT. According to the CMV-DNA test results, children were divided into the CMV-infected group and the CMV-uninfected group. The incidence and risk factors of CMV infection were analyzed. At 1-month post-UCBT, the absolute lymphocyte count, ratio of lymphocyte subsets and immunoglobulin levels were compared between those whose CMV infection developed 1-month later post-UCBT and those not. Mann-Whitney U test and chi-squared test were used for comparision between groups. Kaplan-Meier survival analysis was used to analyze the impact of CMV infection on survival. Results: Among 143 patients, there were 113 males and 30 females, with a age of 14 (8, 27) months at UCBT. Chronic granulomatosis disease (n=49), very-early-onset inflammatory bowel disease (n=43) and severe combined immunodefiency (n=29) were the three main kinds of PID. The rate of CMV infection was 21.7% (31/143), and the time of infection occurring was 44 (31, 49) days post-UCBT. The incidence of recurrent CMV infection was 4.2% (6/143) and refractory CMV infection was 4.9% (7/143).There was no significant difference in the first time CMV-DNA copy and peak CMV-DNA copy during treatment between the recurrent CMV infection group and the non-recurrent CMV infection group (32.8 (18.3, 63.1)×106 vs. 22.5 (13.2, 31.9)×106 copies/L, Z=-0.95, P=0.340;35.2 (20.2, 54.6)×106 vs. 28.4 (24.1, 53.5)×106copies/L, Z=-0.10, P=0.920), so were those between the refractory CMV infection group and non-refractory CMV infection group (21.8 (13.1, 32.2)×106 vs. 25.9 (14.2, 12.2)×106copies/L, Z=-1.04, P=0.299; 47.7 (27.9, 77.6)×106 vs. 27.7 (19.7,51.8)×106copies/L, Z=-1.49, P=0.137). The CMV-infected group accepted more reduced-intensity conditioning (RIC) regimen than the CMV-uninfected group (45.2% (14/31) vs. 25.0% (28/112), χ2=4.76, P<0.05). The rate of CMV-seropositive recipients and Ⅱ-Ⅳ acute graft versus host diseases (aGVHD) are significantly higher in the CMV-infected group than the CMV-uninfected group (100% (31/31) vs. 78.6% (88/112), 64.5% (20/31) vs. 26.8% (30/112), χ2=7.98,15.20, both P<0.05). The follow-up time was 31.6 (13.2, 45.9) months, CMV infection had no effect on overall survival (OS) rate (χ2=0.02, P=0.843). There was significant difference in the survival rate among three groups of refractory CMV infection, non-refractory CMV infection and the CMV-uninfected (4/7 vs.95.8% (23/24) vs. 86.6% (97/112), χ2=5.91, P=0.037), while there was no significant difference in the survival rate among three groups of recurrent CMV infection, non-recurrent CMV infection and the CMV-uninfected (5/6 vs. 88.0% (22/25) vs. 86.6% (97/112), χ2=0.43, P=0.896). Children who developed CMV infection after 30 days post-UCBT had lower absolute count and rate of CD4+ T cells and immunoglobulin G (IgG) level than those in the CMV-uninfected group (124.1 (81.5, 167.6) ×106 vs. 175.5 (108.3, 257.2) ×106/L, 0.240 (0.164, 0.404) vs. 0.376 (0.222, 0.469), 9.3 (6.2, 14.7) vs. 13.6 (10.7, 16.4) g/L, Z=-2.48, -2.12,-2.47, all P<0.05), but have higher rate of CD8+T cells than those in CMV-uninfected group (0.418 (0.281, 0.624) vs. 0.249 (0.154, 0.434), Z=-2.56, P=0.010). Conclusions: RIC regimen, grade Ⅱ-Ⅳ aGVHD and CMV-seropositive recipients are the main risk factors associated with CMV infection in PID patients post-UCBT. Survival rate of children with refractory CMV infection after UCBT is reduced. Immune reconstitution in children after UCBT should be regularly monitored, and frequency of CMV-DNA monitoring should be increased for children with delayed immune reconstitution.

Impact of cytomegalovirus infection prior to hematopoietic stem cell transplantation in children with inborn errors of immunity.

The presence of active viral infections has an impact on the prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT). Nevertheless, the number of reports of cytomegalovirus infection in patients with inborn errors of immunity (IEI) who undergo HSCT is relatively low. To analyze the effect of cytomegalovirus infection acquired prior to curative treatment on patient survival in 123 children with IEI. An observational and retrospective study was performed with patients younger than 18 years diagnosed with IEI who were candidates for HSCT, gene therapy, or thymus transplantation at five hospitals in Spain between 2008 and 2019. We included 123 children, 25 infected by cytomegalovirus prior to undergoing curative treatment (20.3%). At IEI diagnosis, 24 of the patients were already infected, 21 of whom had symptomatic cytomegalovirus disease (87%), while the other three patients developed disease before undergoing curative treatment. The patients with cytomegalovirus infection had higher mortality than those without (p = 0.006). Fourteen patients developed refractory cytomegalovirus infection (56%), all of whom died, while no patients with non-refractory infection died (p = 0.001) All deaths that occurred before curative treatment and three of the five after the treatment were attributed to cytomegalovirus. Patients with refractory cytomegalovirus disease had the highest pre-HSCT mortality rate (64.3%), compared with the non-infected children and those with non-refractory cytomegalovirus disease (10.1%) (p < 0.0001).Conclusion: Prevention and prompt control of cytomegalovirus infection, together with early HSCT/gene therapy, are crucial for improving the prognosis in children with IEI. What is Known:• Cytomegalovirus is the most frequent viral infection in children with inborn errors of immunity who are candidates to hematopoietic stem cell transplantation (HSCT).• Active viral infections at the time of HSCT lead to worse prognosis.What is New:• In children with inborn errors of immunity and indication of HSCT, refractory cytomegalovirus disease is associated with a very high mortality rate, compared with non-infected children and those with non-refractory cytomegalovirus disease.• In patients with novel transplantation indications, the presence and treatment response of CMV infection should be considered to decide the best possible moment for HSCT.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00431-022-04614-5.

P16.38: Healthcare Resource Utilization in Transplant Recipients With Cytomegalovirus Infection Refractory to Prior Treatment With/Without Resistance Receiving Maribavir Versus Investigatorassigned Therapy: Exploratory Analysis of the Phase 3 SOLSTICE Trial

Introduction: Increased healthcare resource utilization (HCRU) has been associated with cytomegalovirus (CMV) infection following transplantation, in particular in patients (pts) requiring >1 antiviral course. In the Phase 3 SOLSTICE study (NCT02931539), maribavir (MBV) was superior to investigator-assigned therapy (IAT; val/ganciclovir, foscarnet, cidofovir) for CMV clearance at Wk 8 and clearance plus symptom control Wk 8 maintained through Wk 16 in transplant recipients with refractory CMV infection with/without resistance (R/R). This exploratory analysis of SOLSTICE evaluated HCRU for the MBV and IAT arms. Methods: Transplant recipients with CMV R/R to prior treatment (failure to achieve >1log10 decrease in CMV DNA after ≥14 days, with/without genotyped resistance) were randomized 2:1 to MBV 400 mg BID or IAT for 8 wks with 12 wks of follow-up. After ≥3 wks of treatment, pts in the IAT arm with pre-specified criteria could enter a MBV rescue arm (8 wks’ MBV treatment, 12 wks’ follow-up). Data on hospital admissions were collected at each study visit and analyzed by treatment during the treatment and follow-up phases. Analyses included the number of pts with ≥1 hospitalization and length of hospital stay (LOS). Hospitalization rates and LOS (per person/year) were estimated using negative binomial models adjusting for exposure time. Adjusted incidence rates (IR), 95% CIs, IR ratios (IRR) and percent reduction in IRRs were calculated. Supplementary analyses described hospitalizations and LOS for the rescue arm and individual IAT groups. Results: In total, 352 pts were randomized (MBV: 235; IAT: 117), of whom 22 (18.8%) entered the MBV rescue arm. While on treatment, pts on MBV versus IAT had reductions of 34.8% in hospitalizations (p=0.021) and 53.8% in LOS (p=0.029; Table). Hospitalization rates were lower during the follow-up than treatment phase, with no differences between treatments in the follow-up (off-treatment) period (Table). The hospitalization rate in the IAT group pre-rescue with MBV (IR=6.98; 95% CI: 4.06, 12.03) was 2.54 times higher (IRR=2.54; 95% CI: 1.28, 5.04; p=0.008) than on or after rescue with MBV (IR=2.75; 95% CI: 1.81, 4.18); increased LOS pre-rescue was also noted (IRR=2.25; 95% CI: 0.72, 7.01) but not statistically significant. In the IAT arm, foscarnet pts tended to have higher hospitalizations (5.5 admissions/person/year) and longer LOS (51.7 days/person/year) during the treatment phase compared with patients on val/ganciclovir or maribavir (Figure). Conclusion: Results from this analysis quantify the HCRU experience of pts requiring treatment for post-transplant CMV. Hospitalizations and LOS were lower for pts on MBV than IAT. Pts who received MBV rescue reported lower hospitalization rates on or after rescue than pre-rescue. Reducing hospitalizations is critical for alleviating disease burden to healthcare systems. TCT2022 encore; DOI pending This study was funded by Takeda Development Center Americas, Inc. Writing and editing support was provided by Caudex (UK), funded by Takeda Development Center Americas, Inc.

Genotypic and Phenotypic Study of Antiviral Resistance Mutations in Refractory Cytomegalovirus Infection.

This study describes the genotypic and phenotypic characterization of novel human cytomegalovirus (HCMV) genetic variants of a cohort of 94 clinically resistant HCMV patients. Antiviral-resistant mutations were detected in the UL97, UL54, and UL56 target genes of 25 of 94 (26.6%) patients. The genotype-phenotype correlation study resolved the status of 5 uncharacterized UL54 deoxyribonucleic acid polymerase (G441S, A543V, F460S, R512C, A928T) and 2 UL56 terminase (F345L, P800L) mutations found in clinical isolates. A928T conferred high, triple resistance to ganciclovir, foscarnet, and cidofovir, and A543V had 10-fold reduced susceptibility to cidofovir. Viral growth assays showed G441S, A543V, F345L, and P800L impaired viral growth capacities compared with wild-type AD169 HCMV. Three-dimensional modeling predicted A543V and A928T phenotypes but not R512C, reinforcing the need for individual characterization of mutations by recombinant phenotyping. Extending mutation databases is crucial to optimize treatments and to improve the assessment of patients with resistant/refractory HCMV infection.

P1617: CLINICAL SIGNIFICANCE OF CYTOMEGALOVIRUS DRUG RESISTANCE GENE MUTATIONS IN CYTOMEGALOVIRUS INFECTION AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background: Cytomegalovirus (CMV) infection is the most important complication after allo-HSCT and threatens the prognosis of patients seriously. Currently, there are limited data on CMV drug-resistant gene mutations in CMV infection after transplantation in China. Aims: In order to further understand the expression of CMV drug-resistant gene mutations in patients with poor efficacy of CMV infection in single center tertiary hematology hospital in china. Methods: The clinical data of 41 patients with CMV infection after allo-HSCT were retrospectively analyzed from January 2019 to July 2021 in transplantation Center of Hematology Hospital, Chinese Academy of Medical Sciences, due to refractory and probable refractory CMV infection, who were tested for CMV resistance gene mutation. The current recommended definitions are based on Guidelines for the management of cytomegalovirus infection from ECIL 7. A total of 21 patients with AML, 8 patients with ALL, 6 patients with AA, 5 patients with MDS and 1 patients with Fanconi anemia are included. Donors were HLA haploid-identical related (N = 36), HLA-identical siblings and un-related (N = 5). Informed consent was obtained. Results: ① Of All 41 patients included, 1 patient (2.4%) had UL97 mutation, 19 patients (46.3%) had UL54 mutation, no patients occur simultaneously with UL54 and UL97 mutation. The overall mutation frequency was 48.8% (20/41), and all mutation types were missense mutation. ② UL54 gene were detected 8 cases of T691S missense mutation (8/41, 19.5%), 3 cases of M827I missense mutation (3/41, 7.3%) and 1 case of A786V missense mutation (1/41, 2.4%). All above these 3 mutation sites had been reported, but the drug resistance significance was unknown. There were 1 site mutation (A543S) of UL97 gene and 19 sites mutation of UL54 gene that had not been reported. The most common mutation site is the T691S mutation in UL54 gene. In all the 41 patients, only one patient exhibited a mutation with definite anti-CMV drug resistance significance: Q578H mutation of UL54 gene, and finally was successfully treated with twice CMV-CTL infusions (figure). ③ Compared with patients without UL54 mutation, patients with UL54 mutation strains had a higher proportion of CMV-DNA re positive rate in 10 days after remission of DNAemia (42.1% vs.9.5%, χ2=5.647, P=0.028), and hadthe significantly longer complete clearance time of CMV DNAemia (40 days vs. 24 days, Z=2.198, P=0.027). ④ Compared with those patients without CMV gene mutation, the patients with T691S mutation had a higher incidence in terms of CMV-DNA turned re positive in 10 days and 14 days after remission of DNAemia (71.4% vs. 19.0%, P=0.008; 71.4% vs. 9.5%, P=0.001; 71.4% vs. 9.5%, P=0.001, respectively). The median time of CMV-DNA reaching the peak was significantly later (14 days vs. 10 days, P=0.016). The median clearance time of CMV DNAemia was significantly longer (56 days vs. 24 days, P=0.002), and the differences were statistically significant. Compared with the non-T691s UL54 mutation, the patients with T691S mutation also had similar results. Image:Summary/Conclusion: CMV gene missense mutations were detected in 48.8% of patients infected with CMV after transplantation, most of which occurred in UL54 gene and T691S mutation is a common missense mutation. The incidence of missense mutations with clear drug resistance was low (2.4%) and might be induced by antiviral therapy. The median clearance time of CMV DNAemia in UL54 mutated patients was significantly longer, and the proportion of CMV-DNA turned re positive was increased, which might be caused by T691S mutation in UL54 gene.

Outcomes of Refractory Cytomegalovirus Infection in the First Year after Allogeneic Hematopoietic Cell Transplantation

Outcomes of refractory (Rf) cytomegalovirus (CMV) infection (CMVi) after hematopoietic cell transplantation (HCT) are poor owing to limited treatment options and treatment related toxicities. Maribavir, an orally bioavailable CMV antiviral, was recently approved for treatment of Rf-CMVi. Real-world studies quantifying the burden of Rf-CMVi prior to maribavir provide a benchmark for evaluating the net value of novel treatments. Here we report the incidence, clinical outcomes, and healthcare resource utilization (HRU) associated with Rf-CMVi in the first year post-HCT in a cohort of CMV-seropositive HCT recipients (R+) who underwent HCT between January 1, 2014, and December 31, 2017, at Memorial Sloan Kettering Cancer Center and were managed exclusively by preemptive therapy. CMVi was defined as CMV viremia treated preemptively. Rf-CMVi was defined as a <1 log10 decrease and CMV viral load >1000 U/mL after ≥14 days of appropriately dosed therapy. Welldays were defined as alive days not hospitalized and off CMV antivirals by 1 year post-HCT. The impact of Rf-CMVi on mortality and HRU was examined in multivariable models. Of the 286 R+ patients, 145 (50.7%) developed CMVi (99 no Rf-CMVi and 46 Rf-CMVi). Compared with the no Rf-CMVi group, the Rf-CMVi group had higher rates of CMV EOD (23.9% versus 10.1%; P=.030), CMV-related mortality (9.5% versus .0%; P=.002), and all-cause mortality (33.3% versus 15.6%; adjusted P=.049). Rf-CMVi was an independent predictor for readmission (adjusted odds ratio [aOR], 3.24; 95% confidence interval [CI], 2.19 to 4.87; P < .0001); CMV-related readmission (aOR, 9.48; 95% CI, 5.83 to 15.80; P < .0001), and decreased well days (adjusted arithmetic mean ratio, .72; 95% CI, .58 to .89; P=.001) in the first year post-HCT. Rf-CMVi is associated with increased mortality and increased HRU at 1 year after HCT. Improved therapies for Rf-CMVi have the potential of improving HCT outcomes and reducing HRU.

Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation.

Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8+ tetramer+ T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

Letermovir treatment for CMV infection in kidney and pancreas transplantation: A valuable option for complicated cases.

Cytomegalovirus (CMV) infection remains a major challenge in solid organ transplantation. Ganciclovir has changed the prognosis, but with the expense of possible viral resistance. New antiviral drugs, such as letermovir, have not been studied sufficiently in kidney and pancreas transplant recipients. We reviewed abdominal organ transplants recipients with CMV infection from the national transplant registry and identified patients treated with letermovir from electronic medical records. We report on letermovir treatment in one kidney and three simultaneous pancreas and kidney (SPK) transplant patients with refractory or ganciclovir-resistant CMV infection (UL54/ UL97 mutation). In SPK patients, persistent leukopenia undermined immunosuppressive and antiviral treatment, favoring life-threatening bacterial infections or ganciclovir resistance. All patients achieved viral clearance after letermovir monotherapy of 1.5-6 months. Letermovir was well tolerated and leukopenia resolved. Adjustments of calcineurin inhibitor doses were challenging. One acute rejection occurred because of under immunosuppression. After the end of treatment, recurrent low-grade CMV-DNAemia was common requiring reinitiating antiviral therapy to achieve viral clearance. To conclude, letermovir was a well-tolerated valuable option for the treatment of refractory or resistant CMV infection in kidney and pancreas transplantation.

21. Efficacy and Safety of Maribavir as a Rescue Treatment for Investigator Assigned Therapy in Transplant Recipients With Refractory or Resistant Cytomegalovirus Infections in the SOLSTICE Study: Phase 3 Trial Results

BackgroundRefractory or resistant (R/R) cytomegalovirus (CMV) infection after hematopoietic cell transplant (HCT) and solid organ transplant (SOT) cause serious, potentially fatal complications; therapeutic options are limited. In a Phase 3 study (NCT02931539), maribavir (MBV) was superior to investigator-assigned therapy (IAT; val/ganciclovir, foscarnet, cidofovir) for CMV clearance (Wk 8) and clearance plus symptom control (Wk 8 through Wk 16) in HCT/SOT recipients with R/R CMV infections. Here we present further study results on efficacy and safety of MBV in the rescue arm.MethodsPatients (pts) were stratified and randomized 2:1 to MBV (400 mg/bid) or IAT for 8-wk treatment then 12-wk follow-up. After minimum 3 wks’ treatment, pts in the IAT group meeting criteria (worsening/lack of improvement of CMV infection or failure to achieve viremia clearance plus IAT intolerance) could enter a MBV rescue arm (8-wk treatment, 12-wk follow-up). In the rescue arm, efficacy was evaluated by confirmed CMV viremia clearance (plasma CMV DNA < 137 IU/mL in 2 consecutive tests ≥ 5 days apart) at end of Wk 8 and confirmed clearance with symptom control at Wk 8 through Wk 16. Safety was assessed.ResultsA total of 352 pts were randomized (MBV: 235, IAT: 117, randomized set). Confirmed CMV viremia clearance at Wk 8 was achieved in 131 (55.7%) and 28 (23.9%) pts, respectively, in the randomized set. Having met criteria, 22 (18.8%) pts entered the MBV rescue arm; at entry, 6 (27.3%) pts had developed neutropenia and 9 (40.9%) had increased serum creatinine (Table 1). At Wk 8 of rescue therapy, 11 (50.0%) pts achieved confirmed CMV viremia clearance; 6 (27.3%) pts had CMV clearance with symptom control at Wk 8 maintained through Wk 16 (Table 2). All 22 pts reported treatment-emergent adverse events (TEAEs; Table 3); most common TEAEs of special interest were nausea, vomiting, and diarrhea (54.5%), and taste disturbance (50.0%). Neutropenia and acute kidney injury TEAEs were reported by 0 and 3 pts in the rescue arm, respectively.Table 1. Summary of patients from IAT-randomized group meeting criteria for entry into MBV rescue arm* Table 2. Patients achieving confirmed CMV viremia clearance at end of Wk 8 (end of treatment) or achieving confirmed CMV viremia clearance and symptom control at end of Wk 8 maintained through Wk 16 Table 3. Treatment-emergent adverse events during the on-rescue observation period ConclusionRescue arm data show MBV was efficacious for R/R CMV infection in HCT/SOT recipients inadequately responding to IAT with/without intolerance and had a similar safety profile to that reported for pts in the randomized MBV group.Disclosures Marcus Pereira, MD, Hologic (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)Takeda (Scientific Research Study Investigator, Advisor or Review Panel member) Carlos Cervera, MD, PhD, Avir Pharma (Consultant, Advisor or Review Panel member)Lilly (Consultant, Advisor or Review Panel member)Merck (Consultant, Advisor or Review Panel member, Research Grant or Support)Sunovion (Consultant, Advisor or Review Panel member)Takeda (Consultant, Advisor or Review Panel member)Veritas Pharma (Consultant, Advisor or Review Panel member) Camille Kotton, MD, Shire/Takeda (Advisor or Review Panel member) Camille Kotton, MD, UpToDate (Individual(s) Involved: Self): I write chapters on zoonoses for UpToDate., Independent Contractor Joseph Sasadeusz, MBBS, PhD, Abbvie (Grant/Research Support, Other Financial or Material Support, Consulting fee: speaker)Gilead (Other Financial or Material Support, Speaker)Merck (Grant/Research Support, Consulting fee: speaker)Takeda (Grant/Research Support) Jingyang Wu, MS, Shire Human Genetic Therapies, Inc., a Takeda company (Employee, Other Financial or Material Support, Holds stock/stock options) Martha Fournier, MD, Shire Human Genetic Therapies, Inc., a Takeda company (Employee, Other Financial or Material Support, Holds stock/stock options)Shire ViroPharma, a Takeda company (Other Financial or Material Support, This study was funded by Shire ViroPharma, a Takeda company)