Valacyclovir reduces rate of fetal CMV infection by 71%
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WASHINGTON — Findings from a randomized, double-blind, placebo-controlled trial presented at IDWeek sparked hope for the use of antiviral medications, specifically valacyclovir, for the prevention of congenital cytomegalovirus, or CMV, infection.
The study found that valacyclovir reduced the rate of fetal CMV infection by 71% in babies born to mothers with evidence of early primary CMV infection.
“As far as we know, to date, our study is the first time that there is any sort of prevention that is shown to be effective,” Keren Shahar-Nissan, MD, a pediatric emergency medicine fellow at Schneider Children’s Medical Center of Israel and a pediatric specialist in the Sackler Faculty of Medicine at Tel Aviv University, told Infectious Diseases in Children.
CMV is common among children, with nearly one in three infected with the virus by age 5 years, according to the CDC. Some infants who were prenatally exposed to the virus can develop neurologic impairment, hearing loss and developmental delays.
A second study presented at IDWeek, a multicenter randomized trial presented by Brenna Hughes, MD, associate professor of obstetrics and gynecology at Duke University, on behalf of the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units Network, showed that a previously promising prevention strategy — CMV hyperimmune globulin (HIG) — may not be as effective as hoped.
Potential preventive strategy
Researchers previously evaluated valacyclovir for safety in pregnant women and their fetuses. In this trial presented at IDWeek, Shahar-Nissan and colleagues randomly assigned 90 pregnant women in a 1:1 ratio to receive either valacyclovir (8 g per day) or placebo. All patients were pregnant and had serologic confirmation of primary CMV infection during the periconceptional period and during the first trimester. Patients continued treatment until amniocentesis.
Shahar-Nissan said Israel was a good location to conduct this study because pregnant women are commonly screened for CMV. Screening in the U.S., she said, is not universally recommended unless findings during pregnancy suggest fetal infection.
Two of the women were pregnant with twins, so the researchers examined 92 amniocentesis results. They found that CMV was more prevalent in the amniotic fluid of women in the placebo group compared with the treatment group (29.8% vs. 11.1%). The odds ratio for vertical transmission was .29 (95% CI, .09-.9), the researchers wrote.
Women infected with CMV during the first trimester and treated with valacyclovir were significantly less likely to have a CMV-positive amniocentesis (n = 2 of 19) compared with the placebo group (n = 11 of 23; P = .02). However, the researchers observed no significant differences in amniocentesis among women infected with CMV in the periconceptional period (P = .91).
Moving forward, Shahar-Nissan said the FDA should approve valacyclovir for congenital CMV prevention. The following step, she said, includes making treatment more patient-friendly.
“Even though we had high compliance rates with women having to take 16 pills a day, it doesn’t have to be 16 pills a day,” she said. “I think the next step needs to be that pharmaceutical companies should make a formulation that is easier to take and that can concentrate in fewer daily pills.”
HIG not protective
A previous phase 2 randomized, placebo-controlled, double-blind trial of HIG was conducted in Italy and published in The New England Journal of Medicine in 2014. The findings demonstrated that although there was a difference in the number of children born with congenital CMV when their mothers were given HIG (n = 18 of 61) compared with placebo (n = 27 of 62), the finding was not statistically significant. This led researchers to conclude that there was no statistical difference between HIG and placebo for this outcome.
Between 2012 and 2018, Hughes and colleagues screened more than 206,000 women with singleton gestation of less than 24 weeks for primary CMV infection. Women who did not transmit — or presumptively transmit — the virus to their fetus received monthly infusions of HIG (100 units per kg) or placebo until delivery.
The researchers identified primary CMV infection in 712 of these women (0.35%), and 56% (n = 399) were enrolled in the trial. Hughes and colleagues noted that the trial was discontinued for futility based on the recommendation of the Data and Safety Monitoring Committee after analysis suggested that a significant outcome was unlikely, even with complete enrollment.
Hughes told Infectious Diseases in Children that there was “no statistically significant difference, but it’s not even a hint of improvement with the administration of hyperimmune globulin.”
Fetal loss or neonatal CMV infection within 3 weeks of birth occurred in 22.7% of women who received HIG and 19.4% who received placebo, the researchers reported (relative risk [RR] = 1.17; 95% CI, 0.8-1,72; P = .42). Women who received HIG had a higher rate of headache (P = .05), as well as shaking and chills (P = .03), compared with women in the placebo group.
The rate of preterm birth also was higher among women who received HIG (12.2% vs. 8.3%; RR = 1.47; 95% CI, 0.81-2.68; P = .02).
“This suggests to us that our hypothesized mechanism of action of this medication potentially preventing congenital CMV is not actually the mechanism,” Hughes said. “We probably need to completely shift gears and look at other ways to prevent transmission rather than this drug.”
She suggested that, like most infectious diseases, the most important prevention strategy would be to develop a vaccine. No vaccine is currently available, but one known as gB/MF59 has completed a phase 2 trial for use in female adolescents aged 12 to 17 years, and a separate phase 2 trial was conducted among women who recently gave birth to prevent infection between pregnancies.
Shannon A. Ross, MD, MSPH, associate professor of pediatrics and microbiology at the University of Alabama at Birmingham, previously told Infectious Diseases in Children that the vaccine had poor efficacy, but other vaccines are in development.
While vaccine development is in process, Hughes said that researchers should begin examining the use of antivirals to decrease the risk for infection or to treat congenital infections. – by Katherine Bortz
References:
CDC. Cytomegalovirus (CMV) and congenital CMV infection: Babies born with CMV. https://www.cdc.gov/cmv/congenital-infection.html. Accessed Oct. 3, 2019.
Hughes B. Abstract LB17. Presented at: IDWeek; Oct. 2-6, 2019; Washington.
Revello MG, et al. N Eng J Med. 2014;doi:10.1056/NEJMoa1310214.
Shahar-Nissan K, et al. Abstract LB20. Presented at IDWeek: Oct. 2-6, 2019; Washington.
Disclosures: Hughes reports consulting for Merck. Shahar-Nissan reports no relevant financial disclosures.