A Cautionary Tale About Treatment of Neonatal Enteroviral Disease

To The Editors: We read with interest the report by Torres-Torres et al1 of the first use of pocapavir for the treatment of neonatal enteroviral disease. The authors report a premature baby with severe neonatal enteroviral sepsis whose symptoms improved with no apparent adverse effects after receiving the investigational drug. The authors concluded that this case provides invaluable initial data for the use of this drug in neonatal enteroviral disease. Does this sound familiar? Like pocapavir, pleconaril is a viral capsid inhibitor, and it has activity against picornaviruses including rhinovirus and enterovirus. Pleconaril was initially developed as a drug for the common cold and was in clinical trials from 1997. Initial results showed pleconaril was generally well tolerated and reduced duration of cold symptoms in adults.2 Concern about menstrual side effects and drug interactions, combined with ambivalence about its clinical benefit resulted in the Food and Drug Administration not approving its use in 2002. Studies ceased but pleconaril use continued on a compassionate basis for severe enterovirus infections. Case reports and case series without controls suggested benefit for life-threatening enteroviral diseases including meningoencephalitis, myocarditis, neonatal enteroviral sepsis and enteroviral infection in the immunocompromised. Our own experience of the largest series of severe neonatal coxsackievirus B sepsis treated with pleconaril found 2 of 7 infants died, comparable to reported untreated mortality.3 Without control data, limited conclusions could be drawn, highlighting the need for drugs of unknown clinical efficacy to be used only as part of a study where data are systematically collected. Further controlled studies were recommended. The only randomized control trial of pleconaril in infants has been in enteroviral meningitis.4 That study was terminated early because of slow recruitment and the sponsor’s decision not to pursue an enteroviral meningitis indication for the drug. No difference was found between treatment and control groups, although with only 21 patients the study was likely underpowered. Since then, pleconaril has been withdrawn from compassionate use. The drug is reportedly now in a phase II clinical study for neonatal enteroviral sepsis.5 Torres-Torres et al’s case report provides useful information about enteroviral susceptibility to pocapavir, serum drug concentrations, and clinical and virologic progress. The authors rightly do not claim efficacy of the drug. Nevertheless it is important that readers learn the lessons of the past and not draw premature conclusions about this drug that is still in a preclinical phase. Only well-powered randomized placebo-controlled trials will provide data on efficacy. In the meantime, clinicians may wish to consider this new drug on a compassionate basis when faced with life-threatening disease. In this era of evidence-based medicine it would be useful to establish an international registry through which data can be systematically collected. Penelope A. Bryant, PhD Nigel Curtis, PhD Paediatric Infectious Diseases Unit Department of General Medicine Murdoch Children’s Research Institute Department of Paediatrics University of Melbourne The Royal Children’s Hospital Melbourne Parkville Victoria, Australia