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F1000Research 2017Congenital cytomegalovirus (CMV) remains a leading cause of disability in children. Understanding the pathogenesis of infection from the mother via the placenta to the... (Review)
Review
Congenital cytomegalovirus (CMV) remains a leading cause of disability in children. Understanding the pathogenesis of infection from the mother via the placenta to the neonate is crucial if we are to produce new interventions and provide supportive mechanisms to improve the outcome of congenitally infected children. In recent years, some major goals have been achieved, including the diagnosis of primary maternal CMV infection in pregnant women by using the anti-CMV IgG avidity test and the diagnosis and prognosis of foetal CMV infection by using polymerase chain reaction real-time tests to detect and quantify the virus in amniotic fluid. This review summarises recent advances in our understanding and highlights where challenges remain, especially in vaccine development and anti-viral therapy of the pregnant woman and the neonate. Currently, no therapeutic options during pregnancy are available except those undergoing clinical trials, whereas valganciclovir treatment is recommended for congenitally infected neonates with moderately to severely symptomatic disease.
PubMed: 28299191
DOI: 10.12688/f1000research.10276.1 -
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 -
Pharmaceutics Jun 2023Ganciclovir and valganciclovir are used for prophylaxis and treatment of cytomegalovirus infection. However, there is great interindividual variability in ganciclovir's...
Ganciclovir and valganciclovir are used for prophylaxis and treatment of cytomegalovirus infection. However, there is great interindividual variability in ganciclovir's pharmacokinetics (PK), highlighting the importance of individualized dosing. To facilitate model-informed precision dosing (MIPD), this study aimed to establish a parametric model repository of ganciclovir and valganciclovir by summarizing existing population pharmacokinetic information and analyzing the sources of variability. (2) Methods: A total of four databases were searched for published population PK models. We replicated these models, evaluated the impact of covariates on clearance, calculated the probability of target attainment for each model based on a predetermined dosing regimen, and developed an area under the concentration-time curve (AUC) calculator using maximum a posteriori Bayesian estimation. (3) Results: A total of 16 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area) and renal function. The results show that 5 mg/kg/12 h of ganciclovir could make the AUC within 40-80 mg·h/L for 50.03% pediatrics but cause AUC exceeding the exposure thresholds for toxicity (120 mg·h/L) in 51.24% adults. (4) Conclusions: Dosing regimens of ganciclovir and valganciclovir should be adjusted according to body size and renal function. This model repository has a broad range of potential applications in MIPD.
PubMed: 37513988
DOI: 10.3390/pharmaceutics15071801 -
Therapeutics and Clinical Risk... 2022Cytomegalovirus (CMV) infections are a common complication in solid organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients, leading to increased morbidity... (Review)
Review
PURPOSE OF REVIEW
Cytomegalovirus (CMV) infections are a common complication in solid organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients, leading to increased morbidity and mortality. Currently available treatment options have reduced the burden of infection, but utilization of these agents can be limited by toxicities such as nephrotoxicity and/or myelosuppression as well as emergence of resistance. The expansion of our current armamentarium towards CMV infection is crucial. Here, we review an emerging therapy, maribavir, and the safety and efficacy of this potential new agent for the prophylaxis and treatment of CMV infections including resistant/refractory disease.
RECENT FINDINGS
Maribavir is a novel agent with CMV activity approved by Federal Food and Drug Administration (FDA) in December 2021 for resistant/refractory disease. Compared to currently available treatment for CMV infection, maribavir has a unique mechanism of action, retains activity against most (val)ganciclovir resistant strains, provides a more predictable pharmacokinetic profile, and fewer severe toxicities. Maribavir has been studied in phase 2 and 3 studies with ongoing phase 3 studies. While maribavir failed to meet the primary endpoints in the initial phase 3 study for prophylaxis therapy in allogeneic-HSCT and liver transplant recipients, results from the phase 2 study when used for pre-emptive therapy after HSCT show similar efficacy to valganciclovir, and results from the phase 3 study examining resistant/refractory disease demonstrate superiority to investigator-initiated therapy of (val)ganciclovir, foscarnet, or cidofovir.
SUMMARY
Maribavir provides a new agent for the management of resistant/refractory CMV infection. Results of the recently published phase 3 study provide further insight into the role of this novel therapy.
PubMed: 35308097
DOI: 10.2147/TCRM.S303052 -
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 -
The National Medical Journal of India 2016
Topics: AIDS-Related Opportunistic Infections; Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Cytomegalovirus Retinitis; Ganciclovir; Humans; Male; Valganciclovir
PubMed: 27492038
DOI: 10.4103/0970-258x.186919 -
Blood Advances Oct 2023Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a...
Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.
Topics: Humans; Adolescent; Adult; Valganciclovir; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Histone Deacetylase Inhibitors; Neoplasm Recurrence, Local; Lymphoma, Non-Hodgkin; Lymphoma; Thrombocytopenia; Lymphoma, T-Cell
PubMed: 37530631
DOI: 10.1182/bloodadvances.2023010330 -
Current Opinion in Pediatrics Feb 2016Cytomegalovirus (CMV) is the most common cause of congenital infection in the world. Symptomatic infants are at increased risk of developing permanent sequelae,... (Review)
Review
PURPOSE OF REVIEW
Cytomegalovirus (CMV) is the most common cause of congenital infection in the world. Symptomatic infants are at increased risk of developing permanent sequelae, including sensorineural hearing loss and neurodevelopmental delay. Advances in the treatment and prevention of congenital CMV infection are a high priority nationally and globally.
RECENT FINDINGS
In symptomatic infants, antiviral therapy with 6 months of oral valganciclovir improves hearing and neurodevelopmental outcomes. Strategies to prevent congenital or maternal CMV infections, including the use of CMV hyperimmune globulin and development of a maternal vaccine, have yet to yield positive results.
SUMMARY
The clinical significance of congenital CMV infection, developments in antiviral therapy, and efforts to prevent congenital disease are herein reviewed.
Topics: Antiviral Agents; Cytomegalovirus Infections; Female; Ganciclovir; Hearing Loss, Sensorineural; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Valganciclovir
PubMed: 26709686
DOI: 10.1097/MOP.0000000000000305 -
Journal of Korean Medical Science Aug 2023The aim of this study was to capture multifaceted clinical characteristics of congenital cytomegalovirus (CMV) infection from diagnosis to treatment using a...
BACKGROUND
The aim of this study was to capture multifaceted clinical characteristics of congenital cytomegalovirus (CMV) infection from diagnosis to treatment using a multidisciplinary approach including obstetrics, pediatrics, pathology, and otorhinolaryngology-head and neck surgery.
METHODS
This is a retrospective study including 30 consecutive cases of congenital CMV infection that were diagnosed at a single tertiary hospital located in Seoul, Korea from January 2009 to December 2020. Congenital CMV infection was defined as a positive result by polymerase chain reaction from urine, saliva or cerebrospinal fluid or positive CMV IgM from neonatal blood sampled within 3 weeks after birth. All cases were analyzed with respect to whole clinical characteristics from diagnosis to treatment of congenital CMV by a multidisciplinary approach including prenatal sonographic findings, maternal immune status regarding CMV infection, detailed placental pathology, neonatal clinical manifestation, auditory brainstem response test, and antiviral treatment (ganciclovir or valganciclovir). Long-term outcomes including developmental delay and hearing loss were also investigated.
RESULTS
The total number of births during the study period in our institution was 19,385, with the prevalence of congenital infection estimated to be 0.15%. Among 30 cases of congenital CMV, the median gestational age at delivery was 32.2 weeks [range, 22.6-40.0] and 66.7% of these infants were delivered preterm at less than 37 weeks. Suspected fetal growth restriction was the most common prenatal ultrasound finding (50%) followed by ventriculomegaly (17.9%) and abnormal placenta (17.9%), defined as thick placenta with calcification. No abnormal findings on ultrasound examination were observed in one-third of births. Maternal CMV serology tests were conducted in only 8 cases, and one case each of positive and equivocal IgM were found. The most common placental pathologic findings were chronic villitis (66.7%) and calcification (63.0%), whereas viral inclusions were identified in only 22.2%. The most common neonatal manifestations were jaundice (58.6%) followed by elevation of aspartate aminotransferase (55.2%) and thrombocytopenia (51.7%). After excluding cases for which long-term outcomes were unavailable due to death (n = 4) or subsequent follow up loss (n = 3), developmental delay was confirmed in 43.5% of infants (10/23), and hearing loss was confirmed in 42.9% (9/21) during the follow-up period. In our cohort, 56.7% (17/30) of neonates were treated for congenital CMV with ganciclovir or valganciclovir.
CONCLUSION
Our data show that prenatal findings including maternal serologic tests and ultrasound have limited ability to detect congenital CMV in Korea. Given that CMV is associated with high rates of developmental delay and hearing loss in infants, there is an urgent need to develop specific strategies for the definite diagnosis of congenital CMV infection during the perinatal period by a multidisciplinary approach to decrease the risks of neurologic impairment and hearing loss through early antiviral treatment.
Topics: Infant; Infant, Newborn; Pregnancy; Female; Humans; Child; Valganciclovir; Retrospective Studies; Placenta; Cytomegalovirus Infections; Ganciclovir; Antiviral Agents; Hearing Loss; Fetal Growth Retardation; Parturition; Immunoglobulin M
PubMed: 37582499
DOI: 10.3346/jkms.2023.38.e249 -
European Annals of Otorhinolaryngology,... Dec 2016Congenital cytomegalovirus (CMV) infection is the second most frequent cause of mental retardation and sensorineural hearing loss, after genetic factors. Recently,... (Review)
Review
Congenital cytomegalovirus (CMV) infection is the second most frequent cause of mental retardation and sensorineural hearing loss, after genetic factors. Recently, pediatric forensic and fetopathological studies have led to progress in understanding the pathophysiological mechanisms underlying the various neurosensory sequelae. Thanks to the identification of certain prognostic factors of hearing loss, therapeutic protocols based on antiviral molecules are now proposed for target populations. This treatment has shown efficacy in limiting hearing threshold deterioration and even, in some cases, seems to provide partial recovery of hearing in symptomatic congenitally infected CMV neonates. However, optimal treatment duration and administration modalities are not clearly defined. This article reviews recent data concerning audiovestibular sequelae and their management in children congenitally infected by CMV.
Topics: Animals; Antiviral Agents; Audiometry; Brain; Cytomegalovirus Infections; Disease Models, Animal; Female; Hearing Loss, Sensorineural; Humans; Pregnancy; Risk Factors; Temporal Bone; Vestibular Diseases; Vestibular Function Tests
PubMed: 27067701
DOI: 10.1016/j.anorl.2016.03.004