Review DOI: Abstract: AbstractCytomegalovirus is the most common congenital infection causing serious disease in infants. It is the leading infectious cause of sensorineural hearing loss and neurodevelopmental disability in developed countries. Despite the clinical importance of congenital cytomegalovirus, surveys show there is limited awareness and knowledge in the medical and general community about congenital cytomegalovirus infection. This article reviews the clinical features, global epidemiology, transmission and risk factors for cytomegalovirus infections.
It also highlights several major advances made in recent years in the diagnosis and prevention of cytomegalovirus infection during pregnancy. Although research is ongoing, no therapy is currently proven to prevent or treat maternal, fetal or neonatal cytomegalovirus infection. Education of women regarding hygiene measures can help prevent cytomegalovirus infection and are currently the best strategy to prevent congenital cytomegalovirus disease.
Classification supporting. Abnormal computed tomography CT scan findings within the first month of life seem to be the best predictor of adverse neurodevelopmental outcomes.
Autopsy results reveal inflammatory infiltrates within the brain parenchyma. They also vary greatly in the degree of disability they cause the patients. Currently, there are four licensed drugs for the systemic treatment of CMV infection: ganciclovir, valganciclovir oral prodrug of ganciclovir , cidofovir and foscarnet. Ganciclovir and valganciclovir are the only two medications that have been employed in the treatment of congenital CMV infection to date, and are the focus of our review. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group CASG conducted a pharmacokinetic—pharmacodynamic study that established the safe dose of intravenous ganciclovir to be administered to infected infants.
Infected newborns were randomized to receive either ganciclovir or no therapy. The primary endpoint was brainstem-evoked response BSER audiometry improvement between baseline and 6 month follow-up, or for those with normal hearing at baseline, preservation of normal hearing at 6 months. Secondary endpoints included laboratory and clinical improvement, rate of growth and death.
At the outset, it should be recognized that the loss to follow-up rate was high and, therefore, denominators for each parameter vary.
However, rigorous evaluation of drops indicated lack of bias in analyses. Forty-three patients were followed and had BSER audiometry at 1 year of age or greater. Secondary outcomes showed significant short-term improvements in weight gain and head circumference in patients who were treated compared with controls. The treated group also had more rapid resolution of their liver function abnormalities. Patients who were treated and those who were not showed similar rates of resolution of hepatosplenomegaly and CMV retinitis. The primary toxicity of ganciclovir, as shown in the previous study, was neutropenia.
This study demonstrates that 6 weeks of intravenous ganciclovir therapy prevents best-ear hearing deterioration during early childhood in patients with symptomatic congenital CMV affecting the CNS. However, the use of ganciclovir should be limited to those children with symptomatic disease, since the medication is mutagenic, teratogenic and carcinogenic. Ganciclovir shows great promise for prevention of poor outcomes from congenital CMV infection, but is difficult to administer because of the requirement of an intravenous infusion. Thus, the administration of valganciclovir, the oral prodrug of ganciclovir, in the treatment of neonates with congenital CMV disease is being explored.
Kimberlin and colleagues 64 , 65 evaluated 24 neonates receiving 6 weeks of therapy with either intravenous ganciclovir or oral valganciclovir. The aim of the study was to assess the population pharmacokinetics of a pharmaceutical-grade oral valganciclovir solution to identify a dose that provided ganciclovir exposure comparable to the administration of intravenous ganciclovir in neonates with symptomatic congenital CMV disease.
In addition, the pharmacodynamic analyses showed a median decrease in viral load of 0. Though results using pharmaceutical-grade valganciclovir cannot be extrapolated to pharmacy-generated formulations, these findings suggest that the oral valganciclovir solution may be a viable option for the treatment of symptomatic congenital CMV infection. Currently, the CASG is performing a controlled clinical trial of 6 weeks versus 6 months of valganciclovir therapy to determine whether a longer duration of treatment results in enhanced hearing and developmental benefits.
Treatment of symptomatic congenital CMV improves audiological outcome. At this time, ganciclovir and its prodrug valganciclovir are the two medications that have been shown to be effective in the treatment of neonates with this common disease. Their use is limited by the potential for toxicity, namely induction of neutropenia, which can be particularly dangerous in neonates who are potentially more susceptible than uninfected or asymptomatic counterparts because of prematurity, residence in intensive care units and, in the case of ganciclovir, the risks of indwelling catheters for drug infusion.
Maribavir, a benzimidazole l -riboside whose mechanism of activity has been mapped to the viral protein products of UL97 and UL27, may provide a new option for the treatment of congenital CMV disease. Maribavir has undergone several Phase I and II studies in haematopoietic stem cell transplant recipients and, unlike ganciclovir, is not associated with nephrotoxicity or haematological toxicities.
Phase III trials have begun in adult patients who have received stem cell and solid organ transplants. Maribavir may provide an alternative with less toxicity than existing medications in the treatment of congenital CMV infection. Ultimately, CMV-associated hearing loss occurs in the vastly larger numbers of asymptomatically infected babies than in the symptomatic group. However, antiviral drugs with improved toxicity profiles are required in order to justify the risk versus benefit of treatment.
In addition to maribavir, other medications with CMV activity and favourable safety profiles are needed in order to achieve maximum therapeutic benefit in this potentially devastating disease. Conceivably, new medications with alternative mechanisms of action may well lead to combination therapies as are employed in the management of AIDS. Congenital CMV infection remains an important cause of neonatal morbidity and mortality and continues to greatly impact the futures of both those who are symptomatic and asymptomatic at birth. Ganciclovir and valganciclovir provide effective reduction in hearing loss and improvement in development of those treated at birth.
These are not perfect drugs, however, as their use is limited by their toxicities and their inability to cure patients of the disease. Future developments of treatments such as maribavir are beneficial, but more research and development can be done to continue to improve the lives of infants who are congenitally infected with CMV. Oxford University Press is a department of the University of Oxford.
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Therapeutics and clinical trials. Unmet medical needs. Transparency declarations. Treatment of congenital cytomegalovirus infection: implications for future therapeutic strategies Lauren Nassetta.
Oxford Academic. Google Scholar. David Kimberlin. Richard Whitley. Cite Citation.
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