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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 -
Ochsner Journal 2019Congenital cytomegalovirus (cCMV) is the leading cause of nongenetic congenital hearing loss in much of the world and a leading cause of neurodevelopmental... (Review)
Review
Congenital cytomegalovirus (cCMV) is the leading cause of nongenetic congenital hearing loss in much of the world and a leading cause of neurodevelopmental disabilities. Infected babies can be born to women who are seropositive and seronegative prior to pregnancy, and the incidence is approximately 0.6%-0.7% in the United States. Symptoms vary from mild to severe, and hearing loss can be delayed in onset and progressive. We reviewed the literature to summarize the epidemiology, clinical manifestations, diagnosis, treatment, and future directions of cCMV. The best way to diagnose the infection is with polymerase chain reaction of urine or saliva within 3 weeks after birth, followed by a repeat confirmatory test if positive. Moderately to severely symptomatic neonates should be treated for 6 months with valganciclovir, and some practitioners also choose to treat infants who have isolated hearing loss only. Treatment is not recommended for asymptomatic infants. All infected infants should be screened for hearing loss and neurodevelopmental sequelae. Universal and targeted screening may be cost effective. Currently, no vaccine is commercially available, although multiple candidates are under study. Congenitally acquired cytomegalovirus is found in all communities around the world with a disease burden that is greater than many other well-known diseases. Advances are being made in prevention and treatment; however, improved awareness of the disease among clinicians and patients is needed.
PubMed: 31258424
DOI: 10.31486/toj.18.0095 -
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 -
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 -
Current Treatment Options in Pediatrics 2022There have been recent advances in the field of congenital CMV infection (cCMV) related to antiviral treatment of pregnant women and infants, the implementation of... (Review)
Review
PURPOSE OF REVIEW
There have been recent advances in the field of congenital CMV infection (cCMV) related to antiviral treatment of pregnant women and infants, the implementation of newborn CMV screening programs, and the frequency and diagnosis of complications among infected children. In addition, postnatal CMV infection (pCMV) is increasingly recognized as a potential cause of long-term sequelae in addition to acute complications among preterm infants, raising important questions related to treatment, and prevention.
RECENT FINDINGS
High-dose valacyclovir appears to be safe and effective for the prevention of cCMV among women with first-trimester primary CMV infection. New studies reveal high rates of vestibular dysfunction and neuropsychiatric manifestations among children with cCMV. Some studies report associations between pCMV and long-term consequences, including neurodevelopmental delay and bronchopulmonary dysplasia, among very low birth weight infants, in addition to high risk of sepsis and death acutely, which has motivated efforts to eliminate the virus from breast milk by different methods.
SUMMARY
More long-term complications of cCMV are increasingly recognized among children previously thought to be asymptomatic. Although a preventive CMV vaccine may be achievable, strategies to reduce the burden of cCMV disease include maternal education about risk-reduction behaviors, antiviral treatment of pregnant women with primary infection, and newborn screening to allow timely, appropriate care. Similarly, although it remains unclear if pCMV causes long-term problems, there is growing interest in identifying and preventing disease from CMV infections among preterm infants.
PubMed: 36465883
DOI: 10.1007/s40746-022-00261-y -
World Journal of Hepatology Feb 2022Cytomegalovirus (CMV) infection is a common complication of liver trans-plantation in children. The CMV serostatus of recipients and donors is the primary risk factor,... (Review)
Review
Cytomegalovirus (CMV) infection is a common complication of liver trans-plantation in children. The CMV serostatus of recipients and donors is the primary risk factor, and prophylaxis or pre-emptive strategies are recommended for high-risk patients. Graft rejection, coinfection and Epstein-Bar virus reactivation, which can lead to post-transplant lymphoproliferative disease, are indirect effects of CMV infection. Assessment of CMV infection viral load should be routinely performed upon clinical suspicion. However, tissue-invasive CMV disease is not associated with CMV viraemia and requires confirmation by tissue pathology. Oral valganciclovir and intravenous ganciclovir are equivalent treatments, and the duration of treatment depends on factors including CMV viral load, tissue pathology, and clinical response. Risk stratification by donor and recipient status prior to transplantation and post-transplantation antiviral prophylaxis or pre-emptive therapy are recommended. Adult guidelines have been established but additional study of the effectiveness of the preventive guidelines in children is needed. This review summarizes the burden, risk factors, clinical manifestations, laboratory evaluation, treatment, and prevention of CMV infection in children after liver transplantation.
PubMed: 35317177
DOI: 10.4254/wjh.v14.i2.338 -
Eye and Vision (London, England) Jan 2021Cytomegalovirus (CMV) can manifest as corneal endotheliitis in immunocompetent individuals. Early diagnosis is prudent to prevent endothelial cell loss, which could... (Review)
Review
BACKGROUND
Cytomegalovirus (CMV) can manifest as corneal endotheliitis in immunocompetent individuals. Early diagnosis is prudent to prevent endothelial cell loss, which could ultimately lead to corneal decompensation. CMV DNA was first detected in an eye with corneal endotheliitis in 2006; since then, clinical evidence from numerous case reports and case series have accumulated.
MAIN TEXT
In this narrative review, we identified several drugs, including ganciclovir, valganciclovir, and their combination in oral, intravenous, intravitreal, and topical forms in different concentrations, together with the judicious use of topical steroids, have reported variable success. There has yet to be any prospective comparative study evaluating the efficacy and safety of these assorted forms of treatment; clinical evidence is based on case reports and case series. CMV endotheliitis presenting with corneal edema can masquerade as other corneal diseases and thus poses a great challenge especially in post-keratoplasty eyes. Heightened awareness is needed before and after keratoplasty to start prompt prophylaxis and treatment.
CONCLUSION
There is no consensus on the management of CMV endotheliitis. Further studies are much needed to elucidate the optimal treatment modality, regime, and duration in the treatment and prophylaxis of CMV endotheliitis.
PubMed: 33441165
DOI: 10.1186/s40662-020-00226-y -
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