Challenges and Opportunities in Developing Respiratory Syncytial Virus Therapeutics
JID
Challenges and Opportunities in Developing Respiratory Syncytial Virus Therapeutics
Eric A. F. Simes
John P. DeVincenzo
Michael Boeckh
Louis Bont
James E. Crowe Jr
Paul Griffiths
Frederick G. Hayden
Richard L. Hodinka
Rosalind L. Smyth
Keith Spencer
Steffen Thirstrup
Edward E. Walsh
Richard J. Whitley
Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence.
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respiratory syncytial virus; therapeutic strategies; patient populations.
Respiratory syncytial virus (RSV) is the single most
important cause of lower respiratory tract infection (LRTI)
in infants and young children worldwide and can cause
LRTI in elderly and immunocompromised patients; it is
associated with significant morbidity and mortality in
these target populations. No effective licensed therapies
are generally available, but existing and emerging
pointof-care diagnostics and investigational RSV-specific
antiviral inhibitors offer promise of progress. In
industrialized countries, RSV receives little publicity and is
not widely recognized by the general public. There is
a common, mistaken belief among drug developers
that RSV is a disease primarily of preterm infants and
that the disease is fundamentally different in term
infants and older children. Furthermore, the adult market
is assumed to be small. This underlines 2 of the
fundamental obstacles that have constrained antiviral product
development: perception of disease severity and clinical
end points. This report summarizes outputs from 2
meetings addressing the challenges in developing RSV
therapeutics.
BURDEN OF RSV INFECTION
Infants and Young Children
By the age of 1 year, 60%70% of children have been infected by
RSV (2%3% of whom are hospitalized) [1], and almost all
children are infected by 2 years [2]. RSV is estimated to cause 33.8
million cases of acute respiratory illness in children <5 years of
age globally, resulting in 2.84.3 million hospital admissions
and 66 000199 000 deaths in 2005 [3]. Most infected infants
experience upper respiratory tract symptoms, but 20%30%
will develop LRTI (bronchiolitis and/or pneumonia).
Bronchiolitis, also known as RSV-associated acute LRTI, is frequently
associated with coinfection with other viral agents, particularly
human rhinovirus infections [48]. Signs and symptoms of
disease include tachypnea, cough, crackles, and wheezing.
Frequently, disease is associated with lethargy, irritability, and
poor feeding. Comorbid factors, which increase the risk of
severe LRTI, include prematurity, cyanotic or complicated
congenital heart disease, chronic lung disease of prematurity,
immunodeficiency, and immunosuppressive therapy (at any
age for the last 2). Some children, including those otherwise
healthy, are at risk for disease progression to respiratory failure,
mechanical ventilation, and intensive care unit management.
The incubation period ranges from 2 to 8 days, but 46 days
is most common.
Because 99% of the deaths reported from RSV in 2005 [3]
occurred in developing countries, reducing the burden of RSV
infections has become a priority of the World Health
Organizations new BRaVe (Battle Against Respiratory Viruses) initiative
[9]. Ongoing population-based surveillance studies in several
emerging countries will provide a platform to more accurately
define the global burden of disease in children. Such data are
beginning to emerge from Kenya and Malaysia, where
lifethreatening disease seems more common than in Europe and
North America [10, 11].
Most infections occur between November and April in
northern temperate locations [12]. In the United States, RSV is
associated with 18% of all respiratory illnesses in children <5 years,
20% of all hospitalizatio (...truncated)