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Transplant International : Official... 2024
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Kidney Transplantation; Transplant Recipients; Valganciclovir
PubMed: 38314399
DOI: 10.3389/ti.2024.11985 -
The Journal of Pediatrics May 2024The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. (Randomized Controlled Trial)
Randomized Controlled Trial
Oral Valganciclovir Initiated Beyond 1 Month of Age as Treatment of Sensorineural Hearing Loss Caused by Congenital Cytomegalovirus Infection: A Randomized Clinical Trial.
OBJECTIVE
The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss.
STUDY DESIGN
We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine.
RESULTS
Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome.
CONCLUSIONS
In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT01649869.
Topics: Humans; Cytomegalovirus Infections; Valganciclovir; Hearing Loss, Sensorineural; Antiviral Agents; Male; Female; Double-Blind Method; Infant; Administration, Oral; Ganciclovir; Child, Preschool; Treatment Outcome; Viral Load; Infant, Newborn
PubMed: 38309519
DOI: 10.1016/j.jpeds.2024.113934 -
Current Opinion in Organ Transplantation Apr 2024Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT). (Review)
Review
PURPOSE OF REVIEW
Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT).
RECENT FINDINGS
Universal prophylaxis and preemptive therapy are the most adopted strategies for prevention of CMV disease globally. Prophylaxis with valganciclovir is the most widely used approach to CMV prevention, however leukopenia and late onset CMV disease after discontinuation of prophylaxis requires new strategies to prevent this complication. The use of assays detecting CMV-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. Letermovir has been recently approved for prophylaxis in kidney transplant recipients. CMV-RNAemia used together with CMV-DNAemia in the viral surveillance of CMV infection provides accurate information on viral load kinetics, mostly in patients receiving letermovir prophylaxis/therapy. The development of refractory and resistant CMV infection remains a major challenge and a new treatment with maribavir is currently available. In the present paper we will review the most recent advances in prevention and treatment of CMV diseases in SOT recipients.
SUMMARY
Recent findings, summarized in the present paper, may be useful to optimize prevention and treatment of CMV infection in SOT.
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Valganciclovir; Transplant Recipients; Organ Transplantation; Acetates; Quinazolines
PubMed: 38288947
DOI: 10.1097/MOT.0000000000001139 -
Infectious Disease Reports Jan 2024Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to... (Review)
Review
Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to viral DNA polymerase inhibitors (val)ganciclovir, foscarnet and cidofovir with a risk for cross-resistance. These drugs may also cause serious side effects. This narrative review provides an update on new antiviral agents that were approved for the prevention and treatment of CMV infections in transplant recipients. Letermovir was approved in 2017 for CMV prophylaxis in CMV-seropositive adults who received an allogeneic hematopoietic stem cell transplant. Maribavir followed four years later, with an indication in the treatment of adult and pediatric transplant patients with refractory/resistant CMV disease. The target of letermovir is the CMV terminase complex (constituted of pUL56, pUL89 and pUL51 subunits). Letermovir prevents the cleavage of viral DNA and its packaging into capsids. Maribavir is a pUL97 kinase inhibitor, which interferes with the assembly of capsids and the egress of virions from the nucleus. Both drugs have activity against most CMV strains resistant to standard drugs and exhibit favorable safety profiles. However, high-level resistance mutations may arise more rapidly in the gene under letermovir than low-grade resistance mutations. Some mutations emerging in the gene under maribavir can be cross-resistant with ganciclovir. Thus, letermovir and maribavir now extend the drug arsenal available for the management of CMV infections and their respective niches are currently defined.
PubMed: 38247977
DOI: 10.3390/idr16010005 -
Transplant Infectious Disease : An... Jun 2024The Comparison of Antiviral Preventative Strategies In Liver Transplant (CAPSIL) study showed pre-emptive therapy (PET) to be superior to antiviral prophylaxis for...
A practical guide to real-world implementation of pre-emptive therapy for Cytomegalovirus disease prevention in high-risk seronegative liver transplant recipients with seropositive donors.
The Comparison of Antiviral Preventative Strategies In Liver Transplant (CAPSIL) study showed pre-emptive therapy (PET) to be superior to antiviral prophylaxis for Cytomegalovirus (CMV) disease prevention in high-risk CMV seronegative liver transplant recipients (LTRs) with seropositive donors (DR). Despite the statistical superiority of PET over prophylaxis in research settings, PET is perceived as a logistically more complex strategy that requires careful coordination of weekly CMV PCR testing, prompt initiation of CMV antivirals upon viremia detection, and timely cessation of antivirals following viremia resolution. Transplant centers may be hesitant to use PET for CMV disease prevention in DR LTRs out of concern that PET coordination is not feasible in clinical practice. We recently described our experience using PET in CMV DR LTRs in a real-world setting, and found it to be as effective for CMV disease prevention as PET performed as part of a clinical trial. Here, we describe a systematic approach for PET implementation in real-world settings and provide practical tools to address anticipated challenges. This framework can support transplant programs in overcoming logistical barriers to PET and incorporating an evidence-based and cost-effective CMV prevention strategy into routine care for high-risk CMV DR LTRs.
Topics: Humans; Cytomegalovirus Infections; Liver Transplantation; Antiviral Agents; Cytomegalovirus; Tissue Donors; Transplant Recipients; Viremia
PubMed: 38214192
DOI: 10.1111/tid.14229 -
Journal of Clinical Medicine Dec 2023(1) Background: CMV infections remain a problem after kidney transplantation, particularly if patients are refractory or resistant (r/r) to treatment with valganciclovir...
(1) Background: CMV infections remain a problem after kidney transplantation, particularly if patients are refractory or resistant (r/r) to treatment with valganciclovir (VGCV) or ganciclovir (GCV). (2) Methods: In a single-center retrospective study, kidney transplant recipients (KTR) receiving letermovir (LTV) as rescue therapy for VGCV-/GCV-r/r CMV disease were analyzed regarding CMV history, immunosuppression, and outcomes. (3) Results: Of 201 KTR treated for CMV between 2017 and 2022, 8 patients received LTV following treatment failure with VGCV/GCV. All patients received CMV prophylaxis with VGCV according to the center's protocol, and 7/8 patients had a high-risk (D+/R-) CMV constellation. In seven of eight cases, rising CMV levels occurred during prophylaxis. In seven of eight patients, a mutation in UL97 associated with a decreased response to VGCV/GCV was detected. In four of eight patients, LTV resulted in CMV clearance after 24 ± 10 weeks (16-39 weeks), two of eight patients stabilized at viral loads <2000 cop/mL (6-20 weeks), and two of eight patients developed LTV resistance (range 8-10 weeks). (4) Conclusion: LTV, which is currently evaluated for CMV prophylaxis in kidney transplantation, also shows promising results for the treatment of patients with VGCV/GCV resistance despite the risk of developing LTV resistance. Additional studies are needed to further define its role in the treatment of patients with CMV resistance.
PubMed: 38202107
DOI: 10.3390/jcm13010100 -
Transplantation Proceedings 2024Prophylactic administration of valganciclovir (VG) is an accepted method for the prevention of cytomegalovirus (CMV) infection after kidney transplantation (KTx). The...
BACKGROUND
Prophylactic administration of valganciclovir (VG) is an accepted method for the prevention of cytomegalovirus (CMV) infection after kidney transplantation (KTx). The standard dosage of oral VG is 900 mg/day, adjusted to renal function. There is growing evidence that low-dose 450 mg/day VG might be safe and effective. We compared low-dose vs standard-dose prophylaxis after KTx in a single-center follow-up study.
METHODS
Data from 603 renal transplantations at a single center were retrospectively analyzed (2011-2014, 12-month follow-up). Recipients with donor IgG positive-recipient IgG positive (D+/R+), (D+/R-), and (D-/R+) CMV serostatus were routinely treated with 450 mg/day VG for 3 months. Based on the same prophylactic dose, patients could be categorized into two groups according to their postoperative renal function: those receiving standard-dose VG due to a lower estimated glomerular filtration rate (eGFR) (average eGFR<60 mL/min/1.73 m) and those receiving low-dose VG due to higher eGFR (average eGFR>60 mL/min/1.73 m).
RESULTS
Estimated glomerular filtration rate-based VG serum alterations significantly affected the risk of CMV infection with a higher incidence in higher VG levels (standard-dose: 357 patients, CMV: 33 cases (9.2 %); low-dose: 246 patients, CMV: 10 cases (4.1%). The occurrence of known risk factors: serologic risk distribution and rate of induction therapy were not statistically different between the 2 groups. Treatment of an acute rejection episode influenced the infection rate significantly in the standard-dose group. As a side effect of prophylaxis, leucopenia (<3G/L) was 2.46 times higher in standard-dose vs low-dose group.
CONCLUSION
Low-dose VG administration is safe and non-inferior to the standard dose in the prophylaxis of CMV infection after KTx.
Topics: Humans; Valganciclovir; Kidney Transplantation; Cytomegalovirus; Antiviral Agents; Retrospective Studies; Ganciclovir; Follow-Up Studies; Cytomegalovirus Infections; Immunoglobulin G
PubMed: 38199858
DOI: 10.1016/j.transproceed.2023.11.021 -
Transplant Infectious Disease : An... Apr 2024Valganciclovir (VGCV) prophylaxis is associated with an increased risk of hematologic side effects. We analyzed the impact of VGCV prophylaxis on leukopenia and...
BACKGROUND
Valganciclovir (VGCV) prophylaxis is associated with an increased risk of hematologic side effects. We analyzed the impact of VGCV prophylaxis on leukopenia and neutropenia rates and explored risk factors for its occurrence.
METHODS
Retrospective cohort study of adult cytomegalovirus (CMV)-seronegative solid organ transplantation (SOT) recipients of either CMV-seropositive (CMV D+/R-) or CMV-seronegative (CMV D-/R-) donors between July 2005 and March 2019. CMV D+/R- SOT recipients received 3-12 months of VGCV prophylaxis whereas CMV D-/R- SOT recipients received no VGCV prophylaxis. Competing risk regression was used to calculate risk factors for significant neutropenia (neutrophil count < 1000/μL).
RESULTS
A total of 430 CMV-seronegative SOT recipients (median age of 52.1 years, 76.5% males) were included, of which 203 (47.2%) were CMV D+/R- and 227 (52.8%) CMV D-/R-. The unadjusted incidence rate ratio of significant neutropenia attributable to VGCV exposure in the first year post-transplant was 13.50 (95% confidence interval 7.36-27.11). Acute rejection occurred more frequently in neutropenic patients at 32.5% compared to 19.1% in those without neutropenia (p = .033). On multivariate analysis, VGCV prophylaxis for 1-90 days and 91-180 days versus no VGCV were the strongest risk factors for significant neutropenia with a sub-distribution hazard ratio of 39.6 (95% CI, 8.57-182.6) and 13.2 (95% CI, 5.46-32.0), respectively.
CONCLUSIONS
VGCV prophylaxis is limited by high rates of neutropenia. Future prospective studies are needed to assess alternative CMV prophylactic strategies in SOT recipients.
Topics: Adult; Male; Humans; Middle Aged; Female; Valganciclovir; Cytomegalovirus; Incidence; Antiviral Agents; Retrospective Studies; Cytomegalovirus Infections; Neutropenia; Organ Transplantation; Ganciclovir; Transplant Recipients
PubMed: 38180285
DOI: 10.1111/tid.14227 -
Transplant Infectious Disease : An... Feb 2024Cytomegalovirus (CMV) infections are a common complication after kidney transplantation (KTx) and negatively affecting patient outcome. Valganciclovir (VGC) prophylaxis...
BACKGROUND
Cytomegalovirus (CMV) infections are a common complication after kidney transplantation (KTx) and negatively affecting patient outcome. Valganciclovir (VGC) prophylaxis is often limited by drug-induced side effects and dose reduction due to decline in kidney function.
METHOD
In the present study, episodes of CMV viremia in the first year after KTx in a cohort of 316 recipients were analyzed retrospectively to identify risk factors linked to persistent infections.
RESULTS
In the studied cohort, 18.7% of patients showed a high-risk (HR) constellation (D+/R-) for CMV infections. CMV viremia affected 22% of our cohort, with HR patients being the most affected cohort (44.1%). Within this group, most viremic events (65.3%) occurred while patients were still on prophylactic therapy, showing significantly higher viral loads and a longer duration compared to seropositive recipients.
CONCLUSION
The analysis at hand revealed that detection of viremia under ongoing antiviral prophylaxis bears an increased risk for sustained viral replication and antiviral drug resistance in HR patients. We identified low estimated glomerular filtration rate (eGFR) and lower dose VGC prophylaxis post-KTx as a risk factor for breakthrough infections in HR patients in our single center cohort. These patients might benefit from a closer CMV monitoring or novel prophylactic agents as letermovir.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Kidney Transplantation; Retrospective Studies; Viremia; Cytomegalovirus Infections; Valganciclovir; Transplant Recipients; Ganciclovir
PubMed: 38180168
DOI: 10.1111/tid.14233 -
BMJ Case Reports Jan 2024We present the case of a man in his 60s with a 5-month medical history of deceased donor liver transplantation, who developed Guillain-Barré syndrome (GBS) secondary to...
We present the case of a man in his 60s with a 5-month medical history of deceased donor liver transplantation, who developed Guillain-Barré syndrome (GBS) secondary to a primary cytomegalovirus (CMV) infection. This was confirmed by molecular tests and serology antibodies that ruled out other frequent aetiologies. Therapy with intravenous immunoglobulin and valganciclovir was started and the patient gradually improved over the weeks. GBS is the most common aetiology of paralysis worldwide, and it is an autoimmune-mediated neuropathy that is frequently caused by a preceding infection. Few cases of GBS have been reported in the context of liver transplant recipients, and those related to CMV infection are extremely rare. This case highlights the importance of considering GBS as a possible differential diagnosis in patients with solid organ transplantation, and it contributes to the knowledge of other infrequent aetiologies of this condition.
Topics: Male; Humans; Cytomegalovirus; Guillain-Barre Syndrome; Liver Transplantation; Living Donors; Cytomegalovirus Infections
PubMed: 38176755
DOI: 10.1136/bcr-2023-255739