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Clinical Transplantation May 2024Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV... (Observational Study)
Observational Study
INTRODUCTION
Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV prophylaxis, its utility can be compromised due to the risk of cytopenia. Letermovir, a novel agent approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients and high-risk kidney transplant recipients, exhibits reduced toxicity. This study aims to present the practical application of letermovir as both primary and secondary prophylaxis against CMV in heart transplant recipients (HTR).
METHODS
In this observational, retrospective, single-center study, we included all consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis. We documented instances of CMV breakthrough infections, side effects related to letermovir, changes in neutropenia following the switch from valganciclovir to letermovir, and any drug interactions with the immunosuppressive regimen.
RESULTS
The study comprised 10 patients: two received primary prophylaxis with letermovir due to a high risk of CMV infection (donor-positive, recipient-negative serostatus), and eight received it as secondary prophylaxis following a CMV infection. The median duration of letermovir administration was 8 months (range 3-12 months). No CMV breakthrough infections were reported while on prophylaxis. However, three patients experienced CMV breakthrough infections after discontinuing letermovir prophylaxis (30%). No significant side effects were observed, although one patient reported digestive intolerance. Among the nine patients on tacrolimus, six needed reduced doses after switching to letermovir.
CONCLUSION
This real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.
Topics: Humans; Cytomegalovirus Infections; Heart Transplantation; Male; Retrospective Studies; Antiviral Agents; Female; Middle Aged; Follow-Up Studies; Cytomegalovirus; Adult; Aged; Prognosis; Acetates; Quinazolines; Transplant Recipients; Postoperative Complications; Risk Factors; Graft Rejection
PubMed: 38686437
DOI: 10.1111/ctr.15327 -
Clinical Drug Investigation Jun 2024Cytomegalovirus (CMV) is a common opportunistic infection after allogenic hematopoietic stem cell transplantation (allo-HSCT). Letermovir, an inhibitor of CMV DNA...
Real-World Safety and Effectiveness of Letermovir in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation: Final Results of Post-Marketing Surveillance in Japan.
BACKGROUND AND OBJECTIVE
Cytomegalovirus (CMV) is a common opportunistic infection after allogenic hematopoietic stem cell transplantation (allo-HSCT). Letermovir, an inhibitor of CMV DNA terminase, is approved for CMV prophylaxis in allo-HSCT patients. We report the final results of post-marketing surveillance of letermovir in Japan.
METHODS
The case report forms were drafted in part by the Japanese Data Center for Hematopoietic Cell Transplantation using data elements in the Transplant Registry Unified Management Program and sent to individual HSCT centers to decrease the burden of reporting. Hematopoietic stem cell transplantation patients who received letermovir between May 2018 and May 2022 were registered. Data collected included physician-assessed adverse events/adverse drug reactions and clinical effectiveness (development of CMV disease, CMV antigen status, and use of preemptive therapy).
RESULTS
A total of 821 HSCT patients were included in the safety analyses. Adverse drug reactions occurred in 11.33% of patients, with serious adverse drug reactions in 3.05%. The five most common adverse drug reactions were nausea (1.58%), renal impairment (1.46%), and acute graft versus host disease, CMV test positive, and hepatic function abnormal (0.61% each). A total of 670 patients were eligible for effectiveness analyses. Among these patients, 16.57% and 28.66% required preemptive therapy through week 14 and week 48, respectively. In addition, relatively few patients developed CMV disease throughout the follow-up period (1.34% at week 14 and 3.85% at week 48).
CONCLUSIONS
This final analysis of post-marketing surveillance with up to 48 weeks follow-up period in Japan provides further evidence supporting the safety profile and effectiveness of letermovir for CMV prophylaxis in patients undergoing allo-HSCT in real-world settings.
PubMed: 38935253
DOI: 10.1007/s40261-024-01376-w -
Transplant Infectious Disease : An... Nov 2023Cytomegalovirus (CMV) is a common cause of morbidity after allogeneic haematopoietic cell transplantation (alloHCT). Pre-emptive therapy (PET) with valganciclovir (VGC)...
BACKGROUND
Cytomegalovirus (CMV) is a common cause of morbidity after allogeneic haematopoietic cell transplantation (alloHCT). Pre-emptive therapy (PET) with valganciclovir (VGC) is associated with haematological toxicity.
METHODS
We included alloHCT patients from 2018 to 2021 where letermovir (LTV) was used for CMV PET because of cytopenias.
RESULTS
Ten patients were included. Six received VGC prior to LTV. VGC was commenced at median d42, given for median 40 days. LTV was commenced at median d90, given for median 54 days. At commencement of antiviral, CMV viral load was higher for VGC at 3.7 log IU/mL, compared to LTV at 2.9 log IU/mL. Viral load reduction occurred at 0.18 log IU/mL per week for VGC, compared to 0.17 log IU/mL per week for LTV. There was no clinically significant CMV viremia after stopping LTV. Cytopenias improved on LTV.
CONCLUSION
LTV was effective in controlling CMV viremia when it was given at a lower starting CMV viral load and later post alloHCT than VGC. Further study is required of LTV as upfront PET following alloHCT.
Topics: Humans; Cytomegalovirus; Antiviral Agents; Viremia; Treatment Outcome; Valganciclovir; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Cytopenia
PubMed: 37676725
DOI: 10.1111/tid.14147 -
Infection & Chemotherapy Mar 2024Cytomegalovirus (CMV) is the most important opportunistic viral pathogen in solid organ transplant (SOT) recipients. The Korean guideline for the prevention of CMV... (Review)
Review
Prevention of Cytomegalovirus Infection in Solid Organ Transplant Recipients: Guidelines by the Korean Society of Infectious Diseases and the Korean Society for Transplantation.
Cytomegalovirus (CMV) is the most important opportunistic viral pathogen in solid organ transplant (SOT) recipients. The Korean guideline for the prevention of CMV infection in SOT recipients was developed jointly by the Korean Society for Infectious Diseases and the Korean Society of Transplantation. CMV serostatus of both donors and recipients should be screened before transplantation to best assess the risk of CMV infection after SOT. Seronegative recipients receiving organs from seropositive donors face the highest risk, followed by seropositive recipients. Either antiviral prophylaxis or preemptive therapy can be used to prevent CMV infection. While both strategies have been demonstrated to prevent CMV infection post-transplant, each has its own advantages and disadvantages. CMV serostatus, transplant organ, other risk factors, and practical issues should be considered for the selection of preventive measures. There is no universal viral load threshold to guide treatment in preemptive therapy. Each institution should define and validate its own threshold. Valganciclovir is the favored agent for both prophylaxis and preemptive therapy. The evaluation of CMV-specific cell-mediated immunity and the monitoring of viral load kinetics are gaining interest, but there was insufficient evidence to issue recommendations. Specific considerations on pediatric transplant recipients are included.
PubMed: 38527780
DOI: 10.3947/ic.2024.0016 -
The Journal of Infectious Diseases Jun 2024We measured cytomegalovirus (CMV)-specific antibodies that neutralize epithelial cell infection (CMV-AbNEIs) in 101 CMV-seropositive kidney transplant recipients (KTRs)...
We measured cytomegalovirus (CMV)-specific antibodies that neutralize epithelial cell infection (CMV-AbNEIs) in 101 CMV-seropositive kidney transplant recipients (KTRs) at baseline and posttransplant months 3 and 6. All the patients received antithymocyte globulin and 3-month valganciclovir prophylaxis. There were no significant differences in pretransplant AbNEIs titers between KTRs that developed or did not develop any-level CMV infection or the composite of high-level infection and/or disease. One-year CMV infection-free survival was comparable between KTRs with or without pretransplant CMV-AbNEIs. No differences were observed by months 3 and 6. We observed no protective role for CMV-AbNEIs among CMV-seropositive KTRs undergoing T-cell-depleting induction.
Topics: Humans; Kidney Transplantation; Cytomegalovirus Infections; Male; Middle Aged; Female; Antibodies, Neutralizing; Antibodies, Viral; Cytomegalovirus; Adult; Transplant Recipients; T-Lymphocytes; Aged; Antiviral Agents; Antilymphocyte Serum; Lymphocyte Depletion; Valganciclovir; Clinical Relevance
PubMed: 37740549
DOI: 10.1093/infdis/jiad411 -
Pediatric Transplantation Mar 2024Valganciclovir is approved for cytomegalovirus prophylaxis in pediatrics using the Pescovitz algorithm. There are reports of valganciclovir overdoses in children with...
BACKGROUND
Valganciclovir is approved for cytomegalovirus prophylaxis in pediatrics using the Pescovitz algorithm. There are reports of valganciclovir overdoses in children with low body surface area and overestimated creatinine clearance utilizing this algorithm. This study compared the incidence of neutropenia and cytomegalovirus infection between the Pescovitz and weight-based dosing algorithms.
METHODS
A single-center retrospective chart review from January 2010 to September 2018 was performed on pediatric heart, liver, and kidney transplant recipients, who received valganciclovir. Data were collected from the initiation of valganciclovir prophylaxis to 30 days after discontinuation. The primary objective was the incidence of neutropenia in patients receiving valganciclovir dosed by the Pescovitz versus weight-based dosing algorithms.
RESULTS
This study included 187 pediatric transplant recipients who received valganciclovir dosed via the Pescovitz (62 recipients) or weight-based dosing algorithms (125 recipients). The incidence of neutropenia was higher in the Pescovitz (69.4%) compared to the weight-based dosing group (53.6%; p = .04) including moderate and severe neutropenia. Cytomegalovirus viremia was not significantly different between the two groups and occurred in 4.8% of the Pescovitz group compared to 2.4% of the weight-based group (p = .4).
CONCLUSIONS
The incidence of neutropenia was greater in recipients receiving valganciclovir dosed via the Pescovitz algorithm compared to the weight-based dosing. There were no significant differences in regard to cytomegalovirus viremia or disease between the two groups.
Topics: Humans; Child; Valganciclovir; Antiviral Agents; Retrospective Studies; Transplant Recipients; Cytomegalovirus Infections; Neutropenia; Organ Transplantation; Viremia; Ganciclovir
PubMed: 38420722
DOI: 10.1111/petr.14714 -
The Journal of Infectious Diseases Jun 2024In a phase 3 trial, letermovir was non-inferior to valganciclovir for CMV disease prophylaxis in CMV-seronegative (R-) kidney transplant recipients (KTRs) who received a...
BACKGROUND
In a phase 3 trial, letermovir was non-inferior to valganciclovir for CMV disease prophylaxis in CMV-seronegative (R-) kidney transplant recipients (KTRs) who received a kidney from a CMV-seropositive donor (D+). Genotypic antiviral resistance and CMV glycoprotein B (gB) genotype are reported.
METHODS
Plasma samples with detectable CMV DNA were sequenced for presence of known letermovir and valganciclovir resistance-associated amino acid substitutions (RASs) encoded by CMV gene regions (UL51, UL56, UL89, UL54, UL97) and prevalence of gB (UL55) genotypes (gB1-gB5).
RESULTS
84 of 292 participants in the letermovir and 93 of 297 in the valganciclovir group had evaluable data for ≥1 gene target. Letermovir RASs were not detected in participants who received letermovir prophylaxis; however, 3 had valganciclovir RASs (pUL97). Twelve participants in the valganciclovir group had valganciclovir RASs (pUL54, pUL97); and 1 who did not receive letermovir during the trial also had letermovir RASs (pUL56). All but 1 participant responded to valganciclovir treatment irrespective of breakthrough CMV DNAemia or frequency of RASs. gB1 was the most frequent genotype across all participants and subgroups.
CONCLUSION
Letermovir RASs were not detected in the letermovir group, supporting a low risk for development of resistance with letermovir prophylaxis in CMV D+R- KTRs.
CLINICAL TRIALS REGISTRATION
ClinicalTrials.gov: NCT03443869, EudraCT: 2017-001055-30.
PubMed: 38853607
DOI: 10.1093/infdis/jiae287 -
Clinical Transplantation Oct 2023Cytomegalovirus (CMV) is a common infection in abdominal transplant recipients (ATR). Prevention of CMV in the highest risk population (CMV IgG donor+/recipient-) is...
BACKGROUND
Cytomegalovirus (CMV) is a common infection in abdominal transplant recipients (ATR). Prevention of CMV in the highest risk population (CMV IgG donor+/recipient-) is critical as CMV is associated with negative outcomes. Guideline recommended prophylactic valganciclovir dosing is 900 mg daily for 6 months in this population. However, reduced dosing strategies are utilized in practice.
METHODS
This single center, retrospective study in adult ATR compared full valganciclovir prophylactic dosing (900 mg daily for 6 months) to reduced dosing (900 mg daily for 3 months, then 450 mg daily for 3 months). The primary endpoint was incidence of CMV infection with viral load >1000 IU/mL. Secondary endpoints included incidence of CMV infection with viral load 200-1000 IU/mL, neutropenia, and leukopenia.
RESULTS
Incidence of CMV infection with viral load >1000 IU/mL (29% vs. 27%, p = 1) or CMV infection with viral load 200-1000 IU/mL (6% vs. 12%, p = .421) did not differ significantly between 68 ATR in reduced and full dosing groups, as well as incidence of leukopenia (94% vs. 97%, p = 1) and neutropenia (77% vs. 70%, p = .586).
CONCLUSIONS
There was no difference in the incidence of CMV infection, neutropenia, or leukopenia of the two dosing regimens, although time to CMV diagnosis was different.
Topics: Adult; Humans; Valganciclovir; Cytomegalovirus; Antiviral Agents; Ganciclovir; Retrospective Studies; Transplant Recipients; Cytomegalovirus Infections; Neutropenia
PubMed: 37256906
DOI: 10.1111/ctr.15041 -
Transplant Infectious Disease : An... Jun 2024The goal was to determine trends in immunosuppression use and its impact on cytomegalovirus (CMV) outcomes over the past 10 years.
BACKGROUND
The goal was to determine trends in immunosuppression use and its impact on cytomegalovirus (CMV) outcomes over the past 10 years.
METHODS
This was a single-center longitudinal cohort study of adult kidney recipients transplanted between Jan 2012 and June 2021. Baseline and follow-up data were gathered via chart abstraction and analyzed using univariate and multivariate analyses.
RESULTS
Of 2392 kidney transplants conducted, 131 patients did not meet inclusion criteria. The mean age was 52 years, 41% were female, 57% were black, and 19% were CMV high-risk. The use of rabbit anti-thymocyte globulin (RATG) induction (odds ratio [OR] 1.6, 1.3-2.1), tacrolimus (FK) level >8 ng/mL (OR 1.1, 1.09-1.11), CMV D+/R- rates (OR 1.06, 1.02-1.10), white blood cell count <3000 (OR 1.22, 1.18-1.26) and valganciclovir prophylaxis (OR 1.7, 1.6-1.9) have significantly increased over the past 10 years. Rejection rates (OR 0.86, 0.82-0.91) and BK viremia >2000 (OR 0.91, 0.91-0.98) have decreased. RATG induction (adjusted hazard ratio [aHR] 1.35, 1.2-1.5), FK >8 ng/mL (aHR 3.5, 3.2-3.9), Belatacept conversion (aHR 2.5, 2.1-3.1), and rejection (aHR 1.8, 1.6-2.0) were significant risk factors for developing CMV infection, while mycophenolate mofetil <1500 mg (aHR 0.52, 0.47-0.59), mammalian target of rapamycin inhibitor (mTORi) conversion (0.77, 0.56-0.89), cyclosporine-A conversion (aHR 0.68, 0.56-0.84) were associated with lower risk of CMV infection.
CONCLUSION
Increasing use of potent immunosuppression coupled with higher CMV D+/R- F rates may be driving higher rates of CMV infection. Cyclosporine and mTORi conversion appears to be protective against CMV. A more individualized immunosuppression regimen based on infection risk merits consideration.
PubMed: 38946207
DOI: 10.1111/tid.14318 -
Therapeutic Drug Monitoring Aug 2023Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of...
BACKGROUND
Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of ganciclovir is often performed; however, clinically established target trough levels corresponding to efficacy are lacking. In 2021, our clinic increased the target trough level for ganciclovir from 1 to 2 mg/L to 2-4 mg/L. This study aims to compare both target trough levels in efficacy, toxicity, and occurrence of resistance.
METHODS
A retrospective cohort study was performed in adult solid organ recipients treated for cytomegalovirus infection with (val)ganciclovir. Clinical efficacy was defined as the absence of treatment failure, defined as > 1 log 10 increase in viral load within 2 weeks of treatment initiation, therapy switch to foscarnet, and/or request for resistance analysis.
RESULTS
A total of 46 patients were involved in the study, with 200 ganciclovir trough levels obtained. The composite endpoint was recorded in 23 (69.7%) and 10 (76.9%) patients in the 1-2 mg/L and the 2-4 mg/L group, respectively ( P = 0.18). No association was found between ganciclovir trough levels and the composite endpoint ( P = 1.0). However, a correlation was found between ganciclovir trough levels and the occurrence of lymphopenia ( P = 0.02).
CONCLUSIONS
Our study could not establish a difference in clinical efficacy or toxicity between target trough levels of 1-2 mg/L or 2-4 mg/L because of the lack of clinical differences between the compared groups. However, a correlation was found between ganciclovir trough levels and lymphopenia, which warrants further investigation.
Topics: Adult; Humans; Ganciclovir; Cytomegalovirus; Antiviral Agents; Retrospective Studies; Drug Monitoring; Cytomegalovirus Infections; Organ Transplantation; Lymphopenia
PubMed: 36730727
DOI: 10.1097/FTD.0000000000001054