PHILADELPHIA – Pleconaril, an oral capsid binder with activity against enterovirus infections, shows promise for the treatment of neonates with enterovirus sepsis, according to findings from a randomized, double-blind, placebo-controlled trial.
Time to culture-negativity for all types of collected specimens combined – including those from the oropharynx, rectum, urine, and serum – was faster in 43 patients treated with 5 mg/kg of pleconaril every 8 hours for 7 days than in18 patients who received placebo (median of 4.0 vs. 7.0 days). The difference approached statistical significance.
Dr. Mark J. Abzug
Fewer subjects in the treatment group remained polymerase chain reaction-positive at last oropharynx sample (83% and 23% were positive on day 1 and at a median of day 14 in the treatment group, vs. 100% and 58%, respectively, in the placebo group), Dr. Mark Abzug of the University of Colorado, Aurora, reported at an annual scientific meeting on infectious diseases.
Mortality in an intention-to-treat analysis was 23% in the treatment group, compared with 44% in the placebo group, and mortality in those with confirmed enterovirus infection was 23% and 42% in the treatment and placebo groups, respectively, Dr. Abzug said at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
Patients were neonates with suspected enterovirus sepsis with illness onset in the first 15 days of life. They were randomized 2:1 to receive active treatment or placebo for 7 days. Specimens were obtained serially for 14 days for viral culture and PCR, pharmacokinetic analysis, and safety evaluations, and clinical assessments were performed over 24 months.
Enterovirus was confirmed by culture or PCR in 43 of the 61 patients, including 31 in the treatment group and 12 in the placebo group. The two groups were similar with respect to baseline characteristics, including median age at illness onset (4.5 and 5.0 days, respectively) and time until enrollment (6 to 7 days into the course of their illness).
Of note, pleconaril concentrations exceeded the 90% inhibitory concentration (IC90) level after the first day of treatment in the treatment group, but 41% of subjects did not achieve this target until after day 4, suggesting the need for a loading dose.
Neonatal enterovirus infections are associated with high morbidity and mortality, and therapy is mainly supportive. While intravenous immunoglobulin is thought to confer potential benefit, it remains unproven, and no specific antiviral therapies are currently available, Dr. Abzug said.
Pleconaril has been shown previously to have activity against most enteroviruses and many rhinoviruses. It is well tolerated: In the current study, treatment-related adverse effects occurred in 1 subject in the treatment group, and in 3 in the placebo group.
While the unexpectedly low yield of viral cultures in this study precluded the demonstration of a difference between the groups with regard to the primary endpoint of day 5 oropharyngeal culture positivity, which was 25% on day 1 and 0% on day 5 in the treatment group, vs. 30% on day 1 and 0% on day 5 in the placebo group, the shorter times to culture and PCR negativity and the suggestion of greater survival in the treatment group are encouraging, Dr. Abzug said.
These indicators of biological and clinical efficacy warrant further investigation of pleconaril for neonatal enteroviral disease, he concluded.The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Abzug reported having no disclosures.