Treatment Of Congenital Cytomegalovirus Infection Research Articles

In utero treatment of congenital cytomegalovirus infection with valganciclovir: an observational study on safety and effectiveness.

The treatment of congenital cytomegalovirus (CMV) infection is usually administered to neonates after birth; however, it can be anticipated during the prenatal period by treating pregnant women in order to reduce the severity of the congenital disease. The most commonly used treatment for CMV during pregnancy is valaciclovir; however, valganciclovir has a higher potency against CMV and is the first choice for neonates with congenital CMV disease. We investigated neonatal and maternal safety of tertiary prevention in infected fetuses showing ultrasound features of infection using valganciclovir. Retrospective cohort study of pregnant women and their symptomatic infected fetuses taking valganciclovir, 3 × 450 mg per day. All fetuses presented at least one prenatal feature on ultrasound. We assessed fetal/neonatal and maternal safety, as well as neonatal efficacy of treatment. The main outcome was neutropenia. Secondary outcomes included other haematological side effects, symptoms at birth and neonatal CMV-PCR was positive. Seventeen women with singleton pregnancies received valganciclovir from a median (IQR) of 27.1 (26.0-30.3) to 11.6 (6.5-12.9) weeks of gestation. No neonatal neutropenia was reported. One pregnancy was terminated for severe features. Three newborns (18%) were asymptomatic at birth, including one with negative CMV-PCR from blood and saliva. CMV-PCR was positive for 12/13 symptomatic newborns, with a median (IQR) log10 viral load of 3.36 (3.30-4.20), 4.03 (1.75-4.27) and 3.04 (0.00-3.40) log10 copies/mL in blood, urine and saliva, respectively. Tertiary prevention by valganciclovir appears to be well tolerated for both fetus and mother. However, more extensive trials accompanied by long-term follow-up are needed.

Congenital cytomegalovirus infection: new answers to old problems

Congenital cytomegalovirus infection is one of the most common TORCH infections, characterized by a wide range of clinical manifestations, predominantly with multiple organ lesions and often a disabling course. The result of antenatal infection with cytomegalovirus is a high incidence of congenital malformations, often accompanied by disorders such as hearing loss, vision loss, motor and cognitive deficits. Despite the presence of modern domestic clinical recommendations, the study of this pathology remains relevant to the present day. Recently, significant progress has been made in the study of this disease. Every year, new research is conducted on topical issues of diagnosis, treatment and rehabilitation for congenital cytomegalovirus infection. This article provides a review of modern literature, covering the latest data on the molecular basis of pathogenesis, features of clinical manifestations, current approaches to the diagnosis and treatment of congenital cytomegalovirus infection.

Treatment of congenital cytomegalovirus infection.

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.

Commentary: Development of Therapeutics for Congenital Cytomegalovirus Infection.

In the mid 1980's, I flew from Birmingham, Alabama to San Francisco, rented a car, and drove to Palo Alto so that I could meet with John Martin at Syntex. John, along with Julian Verheyden, synthesized ganciclovir, which had significant in vitro activity against cytomegalovirus (CMV) in vitro. This drug provided my colleagues and me an opportunity to evaluate it as a therapeutic agent for congenital CMV infection, knowing full well that it was mutagenic, teratogenic, and carcinogenic. John in his wisdom convinced the management of Syntex to provide ganciclovir for this disease, allowing me to study this drug in symptomatic congenitally infected children through the NIAID Collaborative Antiviral Study Group (CASG). Certainly, no other person or company would advocate for the use of such a medication in children, regardless of disease severity, because of its toxicity profile. Since these early days, ganciclovir, and subsequently its prodrug valganciclovir, have become the standard of care for the treatment of congenital cytomegalovirus infection. The following commentary defines the need and progress in the development of therapy.

Case report: congenital cytomegalovirus infection

Background . This review article surveys literature data on the methods of timely diagnosis and treatment of congenital cytomegalovirus infection (CMVI) in newborn infants. In recent years CMVI has become a subject of numerous global-scale studies. Such increased interest in CMVI is due to the fact that the consequences of congenital CMVI have a social impact. Description of clinical case . A clinical case of congenital manifest cytomegalovirus infection is described. The infant was diagnosed with CMVI on the 10th day of life. Complex therapy was prescribed in accordance with the protocol of management of congenital CMVI which led to positive dynamics. Conclusion . By today, an algorithm for detection and treatment of CMVI which brings positive results has been worked out. However, it is essential to keep in mind the long-term sequelae of CMVI and devote close attention to dispensary follow-up of such patients.

Investigational Antiviral Therapy Models for the Prevention and Treatment of Congenital Cytomegalovirus Infection during Pregnancy.

Congenital cytomegalovirus (HCMV) infection may cause significant fetal malformation, lifelong disease, and, in severe cases, fetal or neonatal death. Placental infection with HCMV is the major mechanism of mother-to-child transmission (MTCT) and fetal injury. Thus, any pharmaceutical antiviral interference to reduce viral load may reduce placental damage, MTCT, and fetal disease. However, there is currently no licensed HCMV antiviral for use during pregnancy. In this study, aciclovir and the HCMV-specific antivirals letermovir, maribavir, and cidofovir were compared with ganciclovir for antiviral effects in model systems of pregnancy, including first-trimester TEV-1 trophoblast cell cultures and third-trimester ex vivo placental explant histocultures. HCMV-infected trophoblasts at 7 days postinfection (dpi) showed an EC50 of 21 μM for aciclovir, 0.0007 μM for letermovir, 0.11 μM for maribavir, and 0.29 μM for cidofovir, relative to 0.42 μM for ganciclovir. Antivirals added at 10 μM showed no cytotoxic effects and did not affect trophoblast cell proliferation (P > 0.9999). Multiple-round HCMV replication measured at 7 dpi showed letermovir, maribavir, and cidofovir treatment inhibited immediate early, early, and true late viral protein expression as assayed on Western blots. Antiviral treatment of HCMV-infected placental explants showed significant inhibition (P < 0.05) of viral replication with letermovir (83.3%), maribavir (83.6%), cidofovir (89.3%), and ganciclovir (82.4%), but not aciclovir (P > 0.9999). In ex vivo model systems, recently trialed HCMV antivirals letermovir and maribavir were effective at inhibiting HCMV replication. They partly fulfil requirements for use as safe and effective therapeutics during pregnancy to control congenital HCMV. Clinical trials of these newer agents would assist assessment of their utility in pregnancy.

New evidence on prognostic features, prevention and treatment of congenital Cytomegalovirus infection.

Congenital Cytomegalovirus (CMV) infection remains a major cause of lifelong disability, with no systematic screening implemented in pregnancy or the postnatal period. In this review article, we outline the preventive strategies, antenatal prognostic features and experimental therapies as well as evidence of efficacy from recent trials. A recent randomized, double blinded, placebo-controlled study investigated the efficacy of Valaciclovir in women contracting primary CMV in the periconception period or first trimester. They concluded that Valaciclovir at a dose of 8 g/day is effective in reducing the rate of foetal CMV infection following early maternal primary infection. Administration of CMV hyperimmune globulin (HIG) was investigated in a recent randomized double-masked controlled trial. This study concluded that CMV HIG was ineffective at reducing the risk of congenital CMV among women with primary CMV in early pregnancy. Congenital CMV infection remains a significant cause of disability. There is currently no vaccine available, with the best preventive strategy being patient education on transmission as well as hygiene measures to reduce risk of exposure. Experimental therapies have been investigated in recent years and there is evidence supporting the use of Valaciclovir. Data for the efficacy of CMV HIG remains inconsistent and administration is currently limited to clinical trial settings.

Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection.

Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment. The objective was to investigate the placental transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)). For LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively. Drugs' concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.

Ante- and postnatal diagnostics and complex treatment of congenital cytomegalovirus infection

Timely diagnostics and treatment of cytomegalovirus infection in pregnant women and newborns allow to avoid serious consequences, preserving the life and health of the child. The article provides an example of antenatal diagnosis of congenital cytomegalovirus infection in the fetus (positive result of polymerase chain reaction in umbilical cord blood), treatment with umbilical transfusion of donor red blood cells, postnatal therapy with antiviral drugs, including ganciclovir and specific immunoglobulin. The issues of assessing the risk of congenital cytomegalovirus infection, approaches to its prevention and treatment during pregnancy are discussed.

Transfer Factor Revisited: Treatment of Congenital Cytomegalovirus Infection

A 7-month-old girl with congenital cytomegalovirus (CMV) infection underwent an immune assessment in anticipation of Transfer Factor therapy. She had been symptomatic since birth, with jaundice, rhinorrhea, diarrhea, pneumonia, hepatosplenomegaly, chorioretinitis, hydrocephalus (for which she was shunted), motor retardation, and failure to thrive. Her sputum and urine cultures were positive for CMV and her IgM anti-CMV antibody titer was positive at 1:16-1:32 dilutions. Her baseline immune assessment was normal except for a failure of her peripheral blood mononuclear cells to produce migratory inhibitory factor in response to CMV antigen. Treatment with transfer factor prepared from CMV seropositive donors resulted in clinical improvement, clearance of the virus, normal migratory inhibition factor responses to CMV antigen, and subsequent development of normal growth and development parameters.

Prevalence of Congenital Cytomegalovirus Infection Assessed Through Viral Genome Detection in Dried Blood Spots in Children with Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are neurodevelopmental disorders without a definitive etiology in most cases. Environmental factors, such as viral infections, have been linked with anomalies in brain growth, neuronal development, and functional connectivity. Congenital cytomegalovirus (CMV) infection has been associated with the onset of ASD in several case reports. The aim of this study was to evaluate the prevalence of congenital CMV infection in children with ASD and in healthy controls. The CMV genome was tested by polymerase chain reaction (PCR) on dried blood spots collected at birth from 82 children (38 with ASD and 44 controls). The prevalence of congenital CMV infection was 5.3% (2/38) in cases and 0% (0/44) in controls (p=0.212). The infection rate was about 10-fold higher in patients with ASD than in the general Italian population at birth. For this reason, detection of CMV-DNA on dried blood spots could be considered in the work-up that is usually performed at ASD diagnosis to rule-out a secondary form. Given the potential prevention and treatment of CMV infection, this study could have intriguing consequences, at least for a group of patients with ASD.

Intrauterine Behandlung kongenitaler Zytomegalievirus-Infektionen

Leruez-Ville M et al. In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study. Am J Obstet Gynecol 2016; 215: 462.e1 – 462.e10

OC15.01: In utero treatment of congenital cytomegalovirus infection with Valacyclovir in a multicentre, open‐label, phase II study

OC15.01: <i>In utero</i> treatment of congenital cytomegalovirus infection with Valacyclovir in a multicentre, open‐label, phase <scp>II</scp> study

In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study

Congenital infection with human cytomegalovirus is a major cause of morbidity and mortality. A randomized controlled trial showed that high-dosage valacyclovir prevents cytomegalovirus disease in transplant recipients. Fetuses showing ultrasound features of infection are at high risk of being symptomatic at or before birth. Ina pilot study, oral administration of high-dosage valacyclovir to mothers significantly decreased viral load and produced therapeutic concentrations in the blood of infected fetuses. A randomized controlled trial comparing prenatal treatment with valacyclovir against placebo in infected fetuses failed to recruit because women declined randomization. Randomized controlled trials in fetal medicine have often proven unacceptable by women who decline termination of pregnancy and are not prepared to resign themselves to the odds of the natural history of the disease. We evaluated the efficacy of oral valacyclovir, 8 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, targeting a high-risk group for developing both neurosensory and neurological impairment. We designed a multicenter, open-label, phase II study with 1 arm, using one of Simon's optimal 2-stage designs. Symptomatic fetuses were defined by the presence of measurable extracerebral or mild cerebral ultrasound symptoms. They were treated in utero from prenatal diagnosis at a median of 25.9 weeks' gestation until delivery or termination of pregnancy. Fetuses with severe brain anomalies on ultrasound were not included as were cases completely asymptomatic at presentation, because treatment was unlikely to modify either outcome. The primary endpoint was the proportion of asymptomatic neonates born to treated mothers. At the interim analysis, 8 of 11 women delivered an asymptomatic neonate (required: ≥7). In step 2, 32 additional cases were included for a total of 43; the final number of asymptomatic neonates was 34, more than the 31 required to indicate efficacy according to the Simon 2-stage design. They remained asymptomatic at 12 months. High-dosage valacyclovir given for a median of 89 days to pregnant women carrying a moderately infected fetus was efficient at giving birth to asymptomatic neonates. Fetal blood viral loads decreased and platelet counts increased, both significantly (P= .01 and P < .001, respectively), between treatment initiation and birth after treatment completion, regardless of duration of fetal infection. Compared with a historical cohort obtained by a metaanalysis of the literature, the use of valacyclovir (8 g daily) significantly increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment. Although the pill burden was high (16pills a day) adherence to treatment was >90%. Finally, valacyclovir at this high dosage was extremely well tolerated. Our results indicate that high-dosage valacyclovir given in pregnancy is effective for improving the outcome of moderately symptomatic infected fetuses. Although this study is not a randomized controlled trial, this is the first study reporting the efficacy of an antiviral drug to treat cytomegalovirus-infected fetuses. Moreover, this first study will allow new trials to be conducted, using valacyclovir as a baseline safe and effective treatment in pregnancy, to be compared to the new emerging and more potent anticytomegalovirus drugs that have not currently been tested in pregnancy.

Advances in the prevention and treatment of congenital cytomegalovirus infection.

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. 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. The clinical significance of congenital CMV infection, developments in antiviral therapy, and efforts to prevent congenital disease are herein reviewed.

Viral Load Before and After Exchange Transfusion in a Neonate with Hyperbilirubinemia and Congenital Cytomegalovirus Infection

Introduction: Cytomegalovirus is the most common cause of intrauterine infection in developed countries. Between 10% and 15% of infants infected with congenital cytomegalovirus exhibits the clinically apparent or symptomatic form of the disease. Exchange transfusion is an established therapy for hyperbilirubinemia and severe anemia. However, to the best of our knowledge, the viral load of cytomegalovirus before and after exchange transfusion has not been previously reported. Case report: A Japanese female was delivered at 36 weeks of gestation to a 29-year-old gravida 3 para 3 by emergency Cesarean section because of non-reassuring fetal status. Hepatomegaly, splenomegaly, generalized petechiae, leptocephaly, and jaundice were noted at birth. On admission, her total bilirubin was 14.2 mg/dL, cytomegalovirus immunoglobulin M was positive (4.63 mg/dL), and her head ultrasound and computed tomography showed left intraventricular calcification and bilateral ventriculomegaly. Toxoplasma, rubella, and herpes simplex virus serologies were negative. The exchange transfusion was performed for the treatment of early onset hyperbilirubinemia, not for the treatment of congenital cytomegalovirus infection. The cytomegalovirus viral load before and after exchange transfusion was investigated by real-time polymerase chain reaction, and the plasma viral load of cytomegalovirus was not significantly decreased from before (8.7×105/mL) to after (4.3×105/mL) exchange transfusion. Conclusion: Exchange transfusion did not reduce the viral load of cytomegalovirus in severe congenital cytomegalovirus infection.

29th ESPID Annual Meeting in The Hague, the Netherlands

29th ESPID Annual Meeting in The Hague, the Netherlands

Successful Treatment of Congenital Cytomegalovirus Infection with Valganciclovir

Successful Treatment of Congenital Cytomegalovirus Infection with Valganciclovir

A Neonate with Reduced Cytomegalovirus DNA Copy Number and Marked Improvement of Hearing in the Treatment of Congenital Cytomegalovirus Infection

Congenital cytomegalovirus (CMV) infection can cause severe permanent disabilities. A mother who is seronegative before conception but acquires infection during pregnancy is a risk factor for congenital infection. We describe a neonate in whom congenital CMV infection was diagnosed at birth and confirmed with DNA quantitation by means of the polymerase chain reaction, was accompanied by cerebral ventriculomegaly and severe hearing loss, and was treated with ganciclovir/valganciclovir for 6 weeks. Initially, cerebral ventriculomegaly and calcification were also found with computed tomography, and severe hearing loss was detected with auditory brainstem response testing. After treatment, CMV DNA decreased in copy number and became undetectable. No marked side effects occurred after treatment. Surprisingly, 1 year after treatment, neurological and motor development was equivalent to that in a healthy infant. Audiometry indicated that auditory ability would improve with rehabilitation, speech and language therapy, and cochlear implantation. Single-photon emission computed tomography showed marked improvement 6 months after treatment. This case provides compelling evidence that a reliable diagnosis of congenital CMV infections coupled with a prompt and appropriate treatment program can prevent permanent disability. It is, therefore, important to establish a more effective strategy for the management of congenital CMV infection.

Antiviral Treatment of Cytomegalovirus Infection

Cytomegalovirus (CMV) is an opportunistic pathogen associated with significant morbidity and mortality in immunocompromised hosts. Antiviral agents specifically targeting CMV were initially developed during the human immunodeficiency virus (HIV) epidemic to treat end-organ disease in patients with acquired immunodeficiency syndrome (AIDS). There are currently four antiviral drugs licensed for the treatment of CMV infections: ganciclovir (GCV), valganciclovir (VGCV), foscarnet (FOS), and cidofovir (CDV). The role of these agents has evolved from the treatment of disease to include prevention of CMV infection and disease, primarily in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. The potential use of these drugs is being explored for the treatment of congenital CMV infection, another CMV-associated disease with significant morbidity. The availability of antiviral therapy has provided major advances in the treatment and prevention of CMV infection and has resulted in dramatically improved outcomes for immunocompromised hosts. At the same time, the clinical utility of most of these agents is limited by poor oral bioavailability, associated toxicities, and the potential for development of resistance with extended use. Novel therapeutic agents are needed to address these limitations. In this article, currently available anti-CMV agents will be described. An overview of the clinical syndromes caused by CMV will be provided, with specific reference to the role of antiviral agents in treating and preventing these infections. Antiviral resistance in CMV will be reviewed and novel therapeutic agents that may address resistance will be briefly discussed.