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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 -
British Journal of Clinical Pharmacology Jun 2024Cytomegalovirus (CMV) infection frequently occurs after solid organ transplantation and is associated with an increased morbidity and mortality. Fortunately, the...
Cytomegalovirus (CMV) infection frequently occurs after solid organ transplantation and is associated with an increased morbidity and mortality. Fortunately, the development of valganciclovir prophylaxis has lowered the incidence of CMV infection and its complications in immunosuppressed solid organ transplant recipients. However, breakthrough infections during valganciclovir prophylaxis and late CMV infection after cessation of valganciclovir prophylaxis still occur with the current prophylactic strategy. Additionally, valganciclovir resistance has emerged among CMV strains, which complicates the treatment of CMV infections. Furthermore, the use of valganciclovir is associated with myelotoxicity, which can lead to the premature withdrawal of prophylaxis. It is important to address these current issues in order to improve the standard care after solid organ transplantation. This paper will therefore discuss the clinical practice of valganciclovir prophylaxis, elaborate on its issues and suggest how to improve the current prophylactic strategy with a possible role for therapeutic drug monitoring.
PubMed: 38889884
DOI: 10.1111/bcp.16138 -
Clinical Case Reports Jun 2024The immunomodulatory effect of CMV makes coinfection with other microbes, like VZV possible and potentially deadlier in the post kidney transplant period. Treatment...
KEY CLINICAL MESSAGE
The immunomodulatory effect of CMV makes coinfection with other microbes, like VZV possible and potentially deadlier in the post kidney transplant period. Treatment should be started promptly. Both infections can be treated with Valganciclovir.
ABSTRACT
Infections are common complications in kidney transplant recipients owing to the lifelong immunosuppression. Cytomegalovirus (CMV) and Varicella Zoster Virus (VZV) infections are quite common in the posttransplant period. Coinfection with both however has been reported only once. The immunomodulatory effect of CMV makes their interaction with other organisms like VZV potentially sinister. This is a case of a young woman who developed coinfection with HZV and CMV in the first month following a live related kidney transplantation from her mother. Transplant surgery went well with good urine output, but serum creatinine did not fall below 1.7 mg/dL. Immunosuppression consisted of intravenous (IV), followed by oral prednisolone, Mycophenolate Sodium (MPS) and Tacrolimus. 25 days after an uneventful surgery, she developed fever, followed by pain and vesicular eruption on the forehead, typical of VZV infection, along with rising creatinine. CMV PCR yielded 300 copies/mL of DNA, which was undetectable in both donor and recipient pre-transplant. Total white blood cell count fell to 2 × 10/L. MPS was temporarily stopped. Treatment with Valgancyclovir led to resolution of fever, skin lesions and brought serum creatinine down to baseline over 2 weeks.
PubMed: 38887304
DOI: 10.1002/ccr3.9089 -
Transplant International : Official... 2024Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor...
Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8 T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8 T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3CD8 T cells numbers, while FoxP3CD25, LAG-3 and PD-1 frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV ( = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3CD25 frequencies in CD3CD8 T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3CD25 in CD3CD8 T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3CD25 CD3CD8 T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.
Topics: Humans; Kidney Transplantation; Cytomegalovirus Infections; Female; Male; CD8-Positive T-Lymphocytes; Middle Aged; Forkhead Transcription Factors; Adult; Interleukin-2 Receptor alpha Subunit; Aged; CD3 Complex; Cytomegalovirus; Risk Factors; Transplant Recipients; Graft Survival
PubMed: 38868358
DOI: 10.3389/ti.2024.12963 -
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 -
Journal of Pharmaceutical Health Care... Jun 2024Ganciclovir and its prodrug, valganciclovir, are first-line agents for cytomegalovirus infection prophylaxis after lung transplantation. Although valganciclovir...
BACKGROUND
Ganciclovir and its prodrug, valganciclovir, are first-line agents for cytomegalovirus infection prophylaxis after lung transplantation. Although valganciclovir prophylaxis is known to result in severe leukopenia as an adverse effect, dosage adjustment based on therapeutic drug monitoring (TDM) of ganciclovir concentration is not generally implemented in clinical practice.
CASE PRESENTATION
In this report, we describe the case of a female in her fifties after lung transplantation who successfully maintained valganciclovir prophylaxis under TDM with a minimal occurrence of severe leukopenia. Valganciclovir administration was initiated at a conventional dose of 450 mg/day on postoperative day 43 but was reduced to 450 mg/2 days on postoperative day 69 because of a decrease in white blood cell count and an increase in trough ganciclovir concentration. Subsequently, the valganciclovir dose adjustment was switched from label-indicated renal function-guided dosing to TDM-based dosing, targeting a trough level of 300-800 ng/mL. This target range was determined through deliberations with infectious disease specialists and pharmacists based on previously reported data. The TDM-based dose adjustment successfully prevented cytomegalovirus reactivation without causing significant adverse effects. Valganciclovir prophylaxis was completed on postoperative day 256, and the patient was transferred to another hospital for rehabilitation.
CONCLUSIONS
The findings of the present case suggest that TDM-based dosing could be helpful for clinicians in optimizing the prophylactic administration of valganciclovir in patients undergoing lung transplantation.
PubMed: 38849960
DOI: 10.1186/s40780-024-00352-y -
Journal of Nephrology Jun 2024Kidney transplantation in Sudan is funded by the government. Cytomegalovirus prophylaxis is provided for patients who receive biological induction or have...
BACKGROUND
Kidney transplantation in Sudan is funded by the government. Cytomegalovirus prophylaxis is provided for patients who receive biological induction or have recipient-negative donor-positive cytomegalovirus serology. Doctor Selma Center for Kidney Diseases joined the national kidney transplant program in May 2019. Since then, we observed the frequent occurrence of cancer in patients who received modest immunosuppression without viral prophylaxis.
METHODS
We retrospectively divided kidney transplant recipients between 2019 and 2021 into two groups according to cytomegalovirus prophylaxis and compared tumor occurrence rates.
RESULTS
The first group included 77 patients who did not receive biological induction or cytomegalovirus prophylaxis. The second group included 92 patients who received valganciclovir for 3-6 months. There was no other antiviral treatment except entecavir for chronic hepatitis B virus infection in eight patients. Five patients in the first group developed malignancy. The first patient presented eight months post-transplant with Kaposi sarcoma of the stomach and responded to treatment with sirolimus. The second patient presented nine months post-transplant with cutaneous Kaposi sarcoma and also responded to sirolimus. Two patients presented two and four months post-transplant with aggressive non-cutaneous Kaposi sarcoma that involved the gastrointestinal tract and lymphatic system and died soon afterwards. The fifth patient presented three years post-transplant with non-Hodgkin lymphoma of the duodenum and is currently receiving chemotherapy. Malignancy rate (6.5% vs 0.0%, P = 0.02) and Kaposi sarcoma rate (5.2% vs 0.0%, P = 0.04) were significantly higher in the first group.
CONCLUSION
In Sudan, omitting valganciclovir prophylaxis after kidney transplantation was associated with a high rate of virus-induced malignancy.
PubMed: 38847938
DOI: 10.1007/s40620-024-01978-9 -
Transplantation and Cellular Therapy Jun 2024Preemptive therapy (PET) historically has been the primary strategy to reduce early-onset cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell...
Impact of Primary Letermovir Prophylaxis Versus Preemptive Antiviral Therapy for Cytomegalovirus on Economic and Clinical Outcomes after Hematopoietic Cell Transplantation.
Preemptive therapy (PET) historically has been the primary strategy to reduce early-onset cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplantation (HCT) but is associated with antiviral-associated toxicities and increases in healthcare resource utilization and cost. Despite its high cost, letermovir (LTV) prophylaxis has largely supplanted PET due to its effectiveness and tolerability. Direct comparisons between LTV and PET approaches on economic and clinical outcomes after allogeneic HCT remain limited. Objective: To compare total cost of care (inpatient and outpatient) between LTV prophylaxis and PET through day+180 after allogeneic HCT. Adult allogeneic CMV seropositive (R+) HCT recipients who initiated LTV <30 days after HCT between 01/01/18 and 12/31/18 were matched 1:1 to allogeneic CMV R+ HCT recipients between 01/01/15 and 12/31/17 (PET cohort). Patients were grouped into high-risk (HR) or standard-risk (SR) for CMV to compare the LTV and PET cohorts. Direct costs for each patient's index HCT admission and all subsequent inpatient and outpatient care through day+180 after HCT were determined and converted into 2021 US dollars and then to Medicare proportional dollars (MPD). A secondary analysis using 2019 average wholesale price was conducted to specifically evaluate anti-CMV medication costs. There were a total of 176 patients with 54 HR CMV pairs and 34 SR CMV pairs. No differences in survival between LTV and PET for both HR and SR CMV groups were observed. The rate of clinically significant CMV infection decreased for both HR CMV (11/54, 20.4% versus 38/54, 70.4%, P < .001) and SR CMV (1/34, 2.9% versus 12/34, 35.3%, P < .001) patients who were given LTV prophylaxis with corresponding reductions in val(ganciclovir) and foscarnet (HR CMV only) use. Among HR CMV patients, LTV prophylaxis was associated with reductions in CMV-related readmissions (3/54, 5.6% versus 18/54, 33.3%, P < .001) and outpatient visits within the first 100 days after HCT (20 versus 25, P = .002), and a decreased median total cost of care ($36,018 versus $75,525, P < .001) in MPD was observed. For SR CMV patients on LTV, a significant reduction in the median inpatient cost ($15,668 versus $27,818, P < .001) was found, but this finding was offset by a higher median outpatient cost ($26,145 versus $20,307, P = .030) that was not CMV-driven. LTV prophylaxis is highly effective in reducing clinically significant CMV reactivations for both HR and SR HCT recipients. In this study, LTV prophylaxis was associated with a decreased total cost of care for HR CMV patients through day+180. Specifically, reductions in CMV-related readmissions, exposure to CMV-directed antiviral agents, and outpatient visits in the first 100 days after HCT were observed. SR CMV patients receiving LTV prophylaxis benefited by having a reduced inpatient cost of care due to lowered room and pharmacy costs.
PubMed: 38838781
DOI: 10.1016/j.jtct.2024.05.021 -
Cureus Apr 2024Cytomegalovirus (CMV) is a DNA virus that can cause widespread, severe infection in immunocompromised patients. While CMV usually leads to a subclinical infection in...
Cytomegalovirus (CMV) is a DNA virus that can cause widespread, severe infection in immunocompromised patients. While CMV usually leads to a subclinical infection in immunocompetent individuals, it can rarely cause severe disease in this population. The SARS-CoV-2 virus is an RNA virus and part of the family. SARS-CoV-2 led to the COVID-19 (coronavirus disease 2019) pandemic. Even though COVID-19 usually presents with signs and symptoms of upper respiratory tract infection in younger adults, viral pneumonia, cytopenia, and neurological symptoms become more apparent with increasing age. Herein, we describe an immunocompetent 73-year-old female patient in whom oxygen demand and pancytopenia developed during hospitalization for post-ablation inguinal access site infection. The thorax CT revealed viral pneumonia, but two subsequent SARS-CoV-2 polymerase chain reaction (PCR) tests and a viral respiratory multiplex PCR panel were negative. The CMV viral load was high in the blood sample, and the patient responded to valganciclovir treatment. Although SARS-CoV-2 should be evaluated in patients with viral pneumonia and cytopenia, other viral etiologies mimicking SARS-CoV-2 infection, such as CMV, should not be overlooked in the era of the COVID-19 pandemic.
PubMed: 38817494
DOI: 10.7759/cureus.59360 -
The Annals of Pharmacotherapy May 2024Low-dose valganciclovir (VGC) for cytomegalovirus (CMV) prophylaxis post-transplant has been employed due to cost and safety. The incidence of CMV disease in CMV...
BACKGROUND
Low-dose valganciclovir (VGC) for cytomegalovirus (CMV) prophylaxis post-transplant has been employed due to cost and safety. The incidence of CMV disease in CMV intermediate-risk liver recipients at 1-year after standard-dose prophylaxis is approximately 5%. However, there are limited data on outcomes after using a "true" low-dose VGC prophylaxis regimen in liver and dual-abdominal transplant recipients as VGC was not dose-adjusted in all patients with impaired renal function in prior studies.
OBJECTIVE
The objective was to assess the incidence of CMV associated with low-dose VGC prophylaxis in CMV intermediate-risk liver, simultaneous pancreas-kidney (SPK), and simultaneous liver-kidney (SLK) recipients with creatinine clearance (CrCl) >60 mL/min.
METHODS
This was a retrospective review of CMV intermediate-risk liver, SPK, and SLK recipients with CrCl >60 mL/min transplanted January 2018 to June 2022 who received VGC 450 mg daily for prophylaxis. The primary outcome was incidence of CMV infection 6-months post-transplant.
RESULTS
Ninety-nine transplant recipients were included (79 liver, 11 SPK, 9 SLK). The primary outcome occurred in 13% of patients (liver 10%, SPK 36%, SLK 10%), including 1 case of CMV disease and 3 breakthrough infections. In addition, 6 patients experienced CMV infection between 6-months and 1-year. Recurrence occurred in 3 patients. There was no evidence of CMV resistance. Thirty patients experienced neutropenia within 1-year, 32 were prescribed granulocyte-colony stimulating factors, and 5 experienced thrombocytopenia. Two patients died due to graft-vs-host disease.
CONCLUSION AND RELEVANCE
Low-dose VGC prophylaxis led to comparable CMV infection rates at 6-months in CMV intermediate-risk liver and SLK recipients. However, as SPK recipients displayed higher rates of CMV infection, low-dose VGC should be avoided in this population.
PubMed: 38801191
DOI: 10.1177/10600280241255110