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JAMA Jul 2023Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a...
IMPORTANCE
Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression.
OBJECTIVE
To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022).
INTERVENTIONS
Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos.
MAIN OUTCOMES AND MEASURES
The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.
RESULTS
Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%).
CONCLUSION AND RELEVANCE
Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.
Topics: Adult; Male; Humans; Middle Aged; Female; Antiviral Agents; Valganciclovir; Cytomegalovirus; Kidney Transplantation; Cytomegalovirus Infections; Neutropenia
PubMed: 37279999
DOI: 10.1001/jama.2023.9106 -
Archives of Disease in Childhood Aug 2023Congenital human cytomegalovirus (CMV) infection is the most common congenital infection, affecting around 1 in 200 infants in high-income settings. It can have... (Review)
Review
Congenital human cytomegalovirus (CMV) infection is the most common congenital infection, affecting around 1 in 200 infants in high-income settings. It can have life-long consequences for up to one in four children, including sensorineural hearing loss and neurodisability. Despite the frequency of congenital CMV and the severity for some children, it is a little-known condition by pregnant women, families and healthcare providers. Timely diagnosis of CMV infection in pregnancy is important to facilitate consideration of treatment with valaciclovir, which may reduce the risk of transmission to the fetus or reduce the severity of the outcomes for infected infants. Recognition of features of congenital CMV is important for neonatologists, paediatricians and audiologists to prompt testing for congenital CMV within the first 21 days of life. Early diagnosis gives the opportunity for valganciclovir treatment, where appropriate, to improve outcomes for affected infants. Further research is urgently needed to inform decisions about antenatal and neonatal screening, long-term outcomes for asymptomatic and symptomatic infants, predictors of these outcomes and optimal treatment for women and infants.
Topics: Infant; Infant, Newborn; Child; Female; Pregnancy; Humans; Cytomegalovirus Infections; Valganciclovir; Pregnancy Complications, Infectious; Valacyclovir; Fetal Diseases; Hearing Loss, Sensorineural
PubMed: 36442957
DOI: 10.1136/archdischild-2022-323809 -
Clinical Microbiology and Infection :... Sep 2023Cytomegalovirus (CMV) is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and haematopoietic stem cell transplantation.... (Review)
Review
BACKGROUND
Cytomegalovirus (CMV) is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and haematopoietic stem cell transplantation. Treatment of CMV disease involves a two-pronged approach with antiviral drug treatment coupled with strategies to minimize the intensity of immune suppression.
OBJECTIVES
This narrative review examines the evidence for the current treatment of CMV disease in transplant recipients, including the use of oral antiviral drugs.
SOURCES
Literature search was performed on PubMed with keywords cytomegalovirus, transplantation, ganciclovir, valganciclovir, maribavir, letermovir, cidofovir, and foscarnet.
CONTENT
Intravenous and oral valganciclovir are the standard first-line treatment of cytomegalovirus disease after transplantation. Oral maribavir has demonstrated superior efficacy and safety over CMV DNA polymerase inhibitors for the treatment of refractory or resistant CMV infection. Transplant patients with severe and life-threatening CMV disease, those with very high viral load, and patients with impaired gastrointestinal absorption should still be treated initially with intravenous antiviral drugs, including ganciclovir and foscarnet. Criteria for the safe transition from intravenous therapies to oral antiviral drugs include achieving clinical improvement and satisfactory decline in viral load. Recurrence of CMV viremia and disease is common, particularly among transplant patients who are lymphopenic and have impaired CMV-specific immunity.
IMPLICATIONS
Oral antiviral drugs for the treatment of CMV infection and disease in transplant recipients have improved the CMV landscape, because they reduce the cost and mitigate the inconvenience and risks related to prolonged hospitalization and the need for long-term intravascular access. However, their antiviral efficacy should be complemented by an intentional strategy of reducing the degree of immune suppression to allow for immunologic recovery that ensures durable control of CMV infection.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Valganciclovir; Foscarnet; Transplant Recipients; Ganciclovir; Cytomegalovirus Infections
PubMed: 36963566
DOI: 10.1016/j.cmi.2023.03.020 -
Newborn (Clarksville, Md.) 2023Congenital cytomegalovirus (cCMV) infection is the most common fetal viral infection and contributes to about 25% of childhood hearing loss by the age of 4 years. It is...
Congenital cytomegalovirus (cCMV) infection is the most common fetal viral infection and contributes to about 25% of childhood hearing loss by the age of 4 years. It is the leading nongenetic cause of sensorineural hearing loss (SNHL). Infants born to seroimmune mothers are not completely protected from SNHL, although the severity of their hearing loss may be milder than that seen in those whose mothers had a primary infection. Both direct cytopathic effects and localized inflammatory responses contribute to the pathogenesis of cytomegalovirus (CMV)-induced hearing loss. Hearing loss may be delayed onset, progressive or fluctuating in nature, and therefore, a significant proportion will be missed by universal newborn hearing screening (NHS) and warrants close monitoring of hearing function at least until 5-6 years of age. A multidisciplinary approach is required for the management of hearing loss. These children may need assistive hearing devices or cochlear implantation depending on the severity of their hearing loss. In addition, early intervention services such as speech or occupational therapy could help better communication, language, and social skill outcomes. Preventive measures to decrease intrauterine CMV transmission that have been evaluated include personal protective measures, passive immunoprophylaxis and valacyclovir treatment during pregnancy in mothers with primary CMV infection. Several vaccine candidates are currently in testing and one candidate vaccine in phase 3 trials. Until a CMV vaccine becomes available, behavioral and educational interventions may be the most effective strategy to prevent maternal CMV infection.
PubMed: 38348106
DOI: 10.5005/jp-journals-11002-0081 -
Transplantation Apr 2024Cytomegalovirus (CMV) is one of the most common infections occurring after solid organ transplantation. This high burden of disease, which incurs sizeable morbidity, may... (Review)
Review
Cytomegalovirus (CMV) is one of the most common infections occurring after solid organ transplantation. This high burden of disease, which incurs sizeable morbidity, may be worsening with the proportion of high-risk D+/R- solid organ transplantation recipients increasing in some regions globally. Cohort studies continue to support either universal prophylaxis or preemptive therapy as effective prevention strategies. Letermovir prophylaxis was noninferior to valganciclovir in adult high-risk D+/R- kidney transplant recipients with fewer drug-related adverse events in a recent clinical trial and has now been approved for such use in some regions. Maribavir preemptive therapy failed to demonstrate noninferiority when compared with valganciclovir in hematopoietic stem cell transplant recipients but looked promising for safety. Donor matching could be useful in prevention CMV disease with a survival advantage demonstrated in seronegative recipients waiting up to 30 mo for a seronegative kidney. Immune-guided prophylaxis resulted in fewer CMV infection episodes in lung transplant recipients when compared with fixed-duration prophylaxis in a recent clinical trial. For treatment of refractory or resistant CMV infection, maribavir was more efficacious and better tolerated when compared with investigator-initiated therapy in its registration trial for this condition. Further research regarding best treatment and prophylaxis of resistant or refractory CMV infection is needed to reflect best clinical practice choices. Optimal use of immune globulin or CMV-specific T cells for prevention or treatment of CMV disease remains undefined. Standardized definitions for the design of CMV clinical trials have been developed. In this review, we highlight recent updates in the field from data published since 2018.
Topics: Adult; Humans; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Organ Transplantation; Valganciclovir; Clinical Trials as Topic
PubMed: 37899366
DOI: 10.1097/TP.0000000000004855 -
Clinical Infectious Diseases : An... Mar 2024Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated... (Randomized Controlled Trial)
Randomized Controlled Trial
Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir.
BACKGROUND
Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir.
METHODS
In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed.
RESULTS
Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%).
CONCLUSIONS
Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA].
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Hematopoietic Stem Cell Transplantation; Neutropenia; Valganciclovir; Viremia
PubMed: 38036487
DOI: 10.1093/cid/ciad709 -
Journal of Personalized Medicine Dec 2023Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With... (Review)
Review
Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With the exception of identical twin donor-recipient pairs, lifelong immunosuppression becomes imperative. Unfortunately, immunosuppressant drugs, particularly calcineurin inhibitors like tacrolimus, bring about adverse effects, including nephrotoxicity, diabetes mellitus, hypertension, infections, malignancy, leukopenia, anemia, thrombocytopenia, mouth ulcers, dyslipidemia, and wound complications. Since achieving tolerance is not feasible, patients are compelled to adhere to lifelong immunosuppressive therapies, often involving calcineurin inhibitors, alongside mycophenolic acid or mTOR inhibitors, with or without steroids. : Notably, these drugs, especially calcineurin inhibitors, possess narrow therapeutic windows, resulting in numerous drug-related side effects. This review focuses on the prevalent immunosuppressive drug-related side effects encountered in kidney transplant recipients, namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). Additionally, other post-kidney-transplantation drugs such as valganciclovir may also contribute to adverse events such as leukopenia. For each side effect, we propose preventive measures and outline appropriate treatment strategies.
PubMed: 38138933
DOI: 10.3390/jpm13121706 -
Ugeskrift For Laeger Apr 2024Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for...
Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for therapy-refractory CMV infection or when other treatment options cannot be used. The patient in this case report was a CMV-infected liver transplant recipient, who developed a severe erythema and high CMV DNA during valganciclovir therapy. Toxic epidermal necrolysis was suspected. The patient was treated with maribavir, and both CMV DNA and the skin normalised. This case illustrates that maribavir is a useful alternative to other antiviral drugs for CMV infection.
Topics: Humans; Cytomegalovirus Infections; Liver Transplantation; Antiviral Agents; Ribonucleosides; Benzimidazoles; Male; Middle Aged; Cytomegalovirus; Dichlororibofuranosylbenzimidazole
PubMed: 38708697
DOI: 10.61409/V11230726 -
Clinical and Experimental Pediatrics Sep 2023Congenital cytomegalovirus (CMV) is the most common cause of congenital infection worldwide, the most common nongenetic cause of sensorineural hearing loss in children,...
Congenital cytomegalovirus (CMV) is the most common cause of congenital infection worldwide, the most common nongenetic cause of sensorineural hearing loss in children, and a cause of neurodevelopmental disorders in the brain. Infants with symptomatic congenital CMV infection may benefit from hearing and neurodevelopmental outcomes, particularly if antiviral treatment is initiated within the first month of life. Infants with life-threatening symptoms are recommended to receive 2-6 weeks of intravenous ganciclovir and then switch to oral valganciclovir, and those without life-threatening symptoms are recommended to use oral valganciclovir during the entire 6-month period. During antiviral drug treatment, absolute neutrophil count, platelet count, blood urea nitrogen, creatinine, and liver function tests were performed to identify neutropenia, thrombocytopenia, renal failure, and liver failure. This review investigated the evidence to date of treating congenital CMV infection.
PubMed: 36596746
DOI: 10.3345/cep.2022.01032