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JAMA Apr 2020Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors: A Randomized Clinical Trial.
IMPORTANCE
Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients.
OBJECTIVE
To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease.
DESIGN, SETTING, AND PARTICIPANTS
Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018.
INTERVENTIONS
Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105).
MAIN OUTCOMES AND MEASURES
The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia.
RESULTS
Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46).
CONCLUSIONS AND RELEVANCE
Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01552369.
Topics: Adult; Aged; Antibiotic Prophylaxis; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Female; Humans; Incidence; Liver Transplantation; Male; Middle Aged; Polymerase Chain Reaction; Tissue Donors; Valganciclovir; Viral Load; Viremia
PubMed: 32286644
DOI: 10.1001/jama.2020.3138 -
Journal of the American Society of... May 2023Although cytomegalovirus (CMV) infection is an important factor in the pathogenesis of kidney allograft rejection, previous studies have not determined the optimal CMV... (Randomized Controlled Trial)
Randomized Controlled Trial
SIGNIFICANCE STATEMENT
Although cytomegalovirus (CMV) infection is an important factor in the pathogenesis of kidney allograft rejection, previous studies have not determined the optimal CMV prevention strategy to avoid indirect effects of the virus. In this randomized trial involving 140 kidney transplant recipients, incidence of acute rejection at 12 months was not lower with valganciclovir prophylaxis (for at least 3 months) compared with preemptive therapy initiated after detection of CMV DNA in whole blood. However, prophylaxis was associated with a lower risk of subclinical rejection at 3 months. Although both regimens were effective in preventing CMV disease, the incidence of CMV DNAemia (including episodes with higher viral loads) was significantly higher with preemptive therapy. Further research with long-term follow-up is warranted to better compare the two approaches.
BACKGROUND
The optimal regimen for preventing cytomegalovirus (CMV) infection in kidney transplant recipients, primarily in reducing indirect CMV effects, has not been defined.
METHODS
This open-label, single-center, randomized clinical trial of valganciclovir prophylaxis versus preemptive therapy included kidney transplant recipients recruited between June 2013 and May 2018. After excluding CMV-seronegative recipients with transplants from seronegative donors, we randomized 140 participants 1:1 to receive valganciclovir prophylaxis (900 mg, daily for 3 or 6 months for CMV-seronegative recipients who received a kidney from a CMV-seropositive donor) or preemptive therapy (valganciclovir, 900 mg, twice daily) that was initiated after detection of CMV DNA in whole blood (≥1000 IU/ml) and stopped after two consecutive negative tests (preemptive therapy patients received weekly CMV PCR tests for 4 months). The primary outcome was the incidence of biopsy-confirmed acute rejection at 12 months. Key secondary outcomes included subclinical rejection, CMV disease and DNAemia, and neutropenia.
RESULTS
The incidence of acute rejection was lower with valganciclovir prophylaxis than with preemptive therapy (13%, 9/70 versus 23%, 16/70), but the difference was not statistically significant. Subclinical rejection at 3 months was lower in the prophylaxis group (13% versus 29%, P = 0.027). Both regimens prevented CMV disease (in 4% of patients in both groups). Compared with prophylaxis, preemptive therapy resulted in significantly higher rates of CMV DNAemia (44% versus 75%, P < 0.001) and a higher proportion of patients experiencing episodes with higher viral load (≥2000 IU/ml), but significantly lower valganciclovir exposure and neutropenia.
CONCLUSION
Among kidney transplant recipients, the use of valganciclovir prophylaxis did not result in a significantly lower incidence of acute rejection compared with the use of preemptive therapy.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Optimizing Valganciclovir Efficacy in Renal Transplantation (OVERT Study), ACTRN12613000554763 .
Topics: Humans; Valganciclovir; Antiviral Agents; Kidney Transplantation; Cytomegalovirus Infections; Cytomegalovirus; Neutropenia; Transplant Recipients
PubMed: 36749127
DOI: 10.1681/ASN.0000000000000090 -
Transplantation and Cellular Therapy Jan 2023Letermovir is an attractive cytomegalovirus (CMV) prophylactic agent, but published data in children are scarce. This retrospective chart review aimed to describe our...
Letermovir is an attractive cytomegalovirus (CMV) prophylactic agent, but published data in children are scarce. This retrospective chart review aimed to describe our experience using letermovir as CMV prophylaxis in pediatric hematopoietic cell transplantation (HCT) recipients. Pediatric patients (age <20 years) undergoing allogeneic HCT and receiving letermovir prophylaxis in the Mayo Clinic Pediatric Bone Marrow Transplant Program were eligible for inclusion in this retrospective chart review. Medical records were reviewed to evaluate letermovir dosing, CMV levels, laboratory values, and reports of adverse effects. Between October 2020 and April 2022, 9 patients age 4 to 19 years undergoing allogeneic HCT in the Pediatric Bone Marrow Transplant Program received letermovir prophylaxis, either 240 mg or 480 mg daily at a mean and median dose of 10 mg/kg/day. Letermovir was crushed and administered via nasogastric tube in 4 of 9 patients. Two patients received letermovir for secondary CMV prophylaxis after initial treatment with ganciclovir/valganciclovir, and the remaining 7 received letermovir for primary prophylaxis. One patient, a 20-kg 6-year-old female receiving 240 mg (12 mg/kg), experienced low-level CMV viremia while on letermovir. No other patients experienced CMV reactivation while on letermovir prophylaxis. In 2 patients, transient mild transaminitis was noted within the first weeks of letermovir therapy, which resolved without intervention, and its relationship to letermovir could not be clearly established. Letermovir administration was feasible and well tolerated as CMV prophylaxis in our small cohort of pediatric patients undergoing HCT. Larger, prospective studies are warranted to confirm the safety and efficacy of letermovir in children. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Topics: Female; Humans; Child; Young Adult; Adult; Child, Preschool; Adolescent; Cytomegalovirus; Antiviral Agents; Retrospective Studies; Cytomegalovirus Infections; Valganciclovir
PubMed: 36244677
DOI: 10.1016/j.jtct.2022.10.005 -
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 -
Seminars in Nephrology Sep 2016Cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7 are ubiquitous β-herpesviruses that can cause opportunistic infection and disease in kidney transplant... (Review)
Review
Cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7 are ubiquitous β-herpesviruses that can cause opportunistic infection and disease in kidney transplant recipients. Active CMV infection and disease are associated with acute allograft failure and death, and HHV-6 and HHV-7 replication are associated with CMV disease. CMV prevention strategies are used commonly after kidney transplantation, and include prophylaxis with antiviral medications and preemptive treatment upon the detection of asymptomatic viral replication in blood. Both approaches decrease CMV disease and allograft rejection, but CMV prophylaxis is preferred for high-risk patients because it is easy to administer and may be more effective in real-world settings. CMV disease commonly occurs even with current preventive strategies, whereas HHV-6 and HHV-7 diseases are rare. The clinical manifestations of CMV, HHV-6, and HHV-7 are nonspecific, and laboratory confirmation is essential to establishing diagnoses. Although nucleic acid testing has supplanted other diagnostic modalities given its high sensitivity and specificity, histopathologic examination sometimes is necessary to identify disease definitively. Ganciclovir and valganciclovir are the treatments of choice for CMV and HHV-6, and foscarnet can be used to treat HHV-7. Treatment duration should be informed by the initial severity of disease, and subsequent clinical and virologic responses.
Topics: Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Graft Rejection; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Roseolovirus Infections; Valganciclovir
PubMed: 27772620
DOI: 10.1016/j.semnephrol.2016.05.012 -
Advances in Neonatal Care : Official... Feb 2016Congenital cytomegalovirus (CMV) is the leading viral intrauterine infection in the United States. It causes more developmental delays and long-term sequelae than Down... (Review)
Review
BACKGROUND
Congenital cytomegalovirus (CMV) is the leading viral intrauterine infection in the United States. It causes more developmental delays and long-term sequelae than Down syndrome (trisomy 21), neural tube defects, or fetal alcohol syndrome combined. Yet, this virus, a member of the herpes virus family, is not well known to the public and its prevention is typically not discussed in obstetric offices. Although many infants with congenital CMV are asymptomatic at birth, a significant proportion still may develop sequelae. Symptomatic infants face potentially devastating consequences. Pharmacologic treatment is reserved for those with severe organ or central nervous system involvement. Treatment of infants with congenital CMV can be complex and requires extensive outpatient follow-up.
PURPOSE
To educate nurses and nurse practitioners regarding the risks, signs, treatment, and care related to congenital CMV.
METHODS/SEARCH STRATEGIES
PubMed was searched to obtain English language publications from 2005 to 2015 for studies examining the current knowledge base of congenital cytomegalovirus, sequelae, and subsequent treatment using key terms "cytomegalovirus" combined with "congenital." A total of 18 articles were retained for analysis.
FINDINGS/RESULTS
Overall, the greatest risk reduction strategy for CMV transmission is education of pregnant women. In the neonate at risk for congenital CMV, early identification, antiviral treatment, and care coordination are pivotal to maximizing outcomes.
IMPLICATIONS FOR PRACTICE
Increasing understanding of congenital CMV, modes of transmission, signs of infection, and intervention strategies as well as its impact on development are essential to maximizing outcomes.
IMPLICATIONS FOR RESEARCH
The need for research exists in the area of valganciclovir's impact on sensorineural hearing loss as well as potential vaccines to protect against CMV transmission. Research is also being conducted in the area of passive immunity via administration of CMV-specific hyperimmune globulin therapy to pregnant women diagnosed with a primary CMV infection.
Topics: Adult; Antiviral Agents; Congenital Abnormalities; Cytomegalovirus; Cytomegalovirus Infections; Developmental Disabilities; Female; Ganciclovir; Humans; Immunoglobulins; Immunoglobulins, Intravenous; Infant, Newborn; Male; Nursing Staff; Patient Education as Topic; Pregnancy; Pregnant Women; United States; Valganciclovir; Young Adult
PubMed: 26752783
DOI: 10.1097/ANC.0000000000000242 -
Clinical Pharmacology and Therapeutics Aug 2022Ganciclovir and valganciclovir are first choice drugs for the prevention and treatment of cytomegalovirus infection and disease in solid organ and stem cell transplant... (Review)
Review
Ganciclovir and valganciclovir are first choice drugs for the prevention and treatment of cytomegalovirus infection and disease in solid organ and stem cell transplant recipients. Only a few studies on the pharmacokinetics and exposure/efficacy or exposure/safety relationships of ganciclovir and valganciclovir in transplant recipients have been published so far, and there are still controversies about the exposure parameter to use for therapeutic drug monitoring (TDM). We performed an extensive literature review of the clinical pharmacokinetics data, the exposure/effect relationships in terms of efficacy and safety, and the available tools for valganciclovir and ganciclovir TDM in adults and pediatrics transplant recipients. The pharmacokinetics of ganciclovir and valganciclovir is well described in adults and children, and a high interindividual variability is commonly observed. In contrast, the drug pharmacodynamics has been poorly described in adults and barely in children. The average 24-hour area under the concentration-time curve (AUC ) seems to be the best predictor of efficacy and toxicity. The benefit of TDM remains controversial in adult patients but should be considered in children due to higher interindividual variability and lower probability of target attainment. Several bayesian estimators based on limited sampling strategies have been developed with this aim and may be used in clinical practice for the AUC-based individual dose adjustment of ganciclovir and valganciclovir.
Topics: Adult; Antiviral Agents; Bayes Theorem; Child; Drug Monitoring; Ganciclovir; Humans; Organ Transplantation; Valganciclovir
PubMed: 34596243
DOI: 10.1002/cpt.2431 -
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 -
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 -
Children (Basel, Switzerland) Jul 2023Cytomegalovirus (CMV) is the most common agent of congenital infection in humans. It is a main cause of neurodevelopmental delay and sensorineural hearing loss in... (Review)
Review
BACKGROUND
Cytomegalovirus (CMV) is the most common agent of congenital infection in humans. It is a main cause of neurodevelopmental delay and sensorineural hearing loss in infancy. Since the 2000s, a number of studies have used Valganciclovir as a therapy for children with congenital CMV infection.
METHODS
In order to evaluate the efficacy of Valganciclovir in preventing clinical sequelae and its possible side effects, we performed a review of the published literature. This search was completed via PubMed for manuscripts published from January 2007 to December 2021, combining the MeSH words "Valganciclovir", "Congenital", and "Cytomegalovirus".
RESULTS
A total of 27 articles were included (12 retrospective studies, 4 prospective studies, 1 randomized controlled trial, and 10 case reports). The clinical features were similar to those already described in the literature. The therapeutic protocols used were very different between the various studies included and neonatal antiviral treatments were only moderately effective. The therapy proved to be well-tolerated.
CONCLUSIONS
The quality of the included studies and the sample size were limited due to the rarity of the disease. The use of different therapeutic protocols in terms of starting dates, doses, and durations made it impossible to compare and correctly evaluate the efficacy of the treatments. Randomized controlled trials are needed to establish the correct effective dose with the fewest side effects and the most efficient duration of therapy.
PubMed: 37508743
DOI: 10.3390/children10071246