Inside Pediatrics Winter 2017

and could provide evidence that the outcome of congenital CMV could be modified by antiviral drugs. Prior to valganciclovir, symptomatic babies were treated with the intravenous drug ganciclovir. As antiviral drugs became available in the 1980s, Alford and Whitley approached the company that made ganciclovir and convinced the company to allow the drug to be studied for treating congenital CMV. When Kimberlin joined the division in the 1990s, he began work on an ongoing study spearheaded by Whitley and completed a phase 3 controlled study that determined ganciclovir improved outcomes when administered to symptomatic babies for six weeks. With the arrival of oral valganciclovir, a later study found six months of oral drug therapy for symptomatic babies improved audiologic and neurodevelopmental outcomes. The results were published in the New England Journal of Medicine in 2015. “By showing long-term treatment in babies with symptomatic disease improves hearing and development, we definitively answered one question that had been raised three decades before – Does treating symptomatic congenital CMV work?” Kimberlin said. “In this new study of asymptomatic infants, we will treat for four months because our hypothesis is asymptomatic babies are not as sick, therefore, we can treat over a shorter time frame.” To identify asymptomatic babies for the new study, almost 50,000 babies will be screened at nine sites nationwide, including UAB/Children’s. Once those babies are identified and enrolled, researchers will compare their findings to past data to determine the likelihood of asymptomatic babies developing hearing loss. Screening for the new study is slated to begin late 2017. “If those incident rates overlap, then maybe treatment doesn’t help very much at all. But if the incidents don’t overlap, then it would suggest the treatment may be helping,” Kimberlin said. Universal Testing & Ongoing Work “A targeted CMV approach that tests newborns who fail their [newborn hearing screening (NHS)] identified the majority of infants with CMV-related [hearing loss] at birth,” the CHIMES Study concludes. “However, 43 percent of the infants with CMV-related [hearing loss] in the neonatal period and CMV infants who are at risk for late onset [hearing loss] were not identified by NHS.” All in the division believe the medical field is moving toward universal testing for CMV, and that will result in identifying more asymptomatic babies. “There’s going to be a real pressure on doctors to treat those babies,” said Kimberlin, who added data gathered from the new asymptomatic study might inform that pressure and whether it is appropriate to do so. New data could coincide with the adoption of universal testing or, at least, adoption on a state-by-state basis. “We have a window of time that’s probably pretty finite before people start feeling the pressure.” The CHIMES Study sample bank allows Ross and Scott James, M.D., to study CMV in various parts of the body. They use next generation sequencing or deep sequencing to identify viral subpopulations with diminished resistance to antiviral drugs. “My main interest is looking at predictors of outcome for the virus and the patient, and the constellation of symptoms to let us know which babies will have hearing loss,” Ross said. “Deep sequencing generates a lot of genetic

data on the virus, or mutations in the virus that may give us hints about hearing loss risk.” Boppana and Britt also document the impact of CMV in highly seropositive settings, including developing countries. Studies have been conducted in India and Brazil, and ongoing studies are under way in Brazil and South Africa. The division also evaluates new antiviral drug therapies for diseases other than CMV via the Collaborative Antiviral Study Group, an NIH multicenter clinical trials group Alford and Whitley established in the 1970s. Each niche of research moves the needle toward better understanding prevention, diagnosis, prognosis and management. “To see the knowledge generated within these walls and its impact on families is a very gratifying thing, but it also gets us a bit impatient sometimes because we know where it needs to be,” Kimberlin said. “We know where we need to go.” Raising Awareness In addition to the CHIMES Study, Fowler and Boppana are involved with the National CMV Foundation, whose mission is education on specific prevention measures to protect against the risk of infection. Statistics show about 30 to 50 percent of women of childbearing age in the U.S. have never been infected with CMV. Of these, about 1 to 4 percent will have their first CMV infection during a pregnancy, giving them approximately a 40 percent chance of passing the virus to their unborn child. According to the foundation, only 9 percent of women know about CMV. “Nobody mentions CMV until they have to. And when it is mentioned, parents say, ‘What is that?’” Fowler said. “We must simplify the message for mothers and for women.” Kimberlin agrees, adding patients and families who share their congenital CMV experience have an impactful message. “We feel like what we do contributes to the lives of children, and as these studies go on, bonds have developed between each of us as researchers and the families affected by this,” Kimberlin said. “Parent advocacy amplifies the power of what we do. A parent advocating for their own child is a magnitude different from researchers who are trying to raise awareness about a disease they feel strongly about.”

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