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Review Antivirals Against Enteroviruses: a Critical Review from a Public-Health Perspective

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Review Antivirals Against Enteroviruses: a Critical Review from a Public-Health Perspective Antiviral Therapy 2015; 20:121–130 (doi: 10.3851/IMP2939) Review Antivirals against enteroviruses: a critical review from a public-health perspective Kimberley SM Benschop1*, Harrie GAM van der Avoort1, Erwin Duizer1, Marion PG Koopmans1,2 1Centre for Infectious Diseases Research, Diagnostics and Screening, National Institute for Public Health and the Environment, Bilthoven, the Netherlands 2Department of Viroscience, Erasmus Medical Centre, Rotterdam, the Netherlands *Corresponding author e-mail: [email protected] The enteroviruses (EVs) of the Picornaviridae family are potential emergence of drug-resistant strains and their the most common viral pathogens known. Most EV infec- impact on EV transmission and endemic circulation. We tions are mild and self-limiting but manifestations can include non-picornavirus antivirals that inhibit EV rep- be severe in children and immunodeficient individuals. lication, for example, ribavirin, a treatment for infection Antiviral development is actively pursued to benefit these with HCV, and amantadine, a treatment for influenza A. high-risk patients and, given the alarming problem of They may have spurred resistance emergence in HCV or antimicrobial drug resistance, antiviral drug resistance influenza A patients who are unknowingly coinfected is a public-health concern. Picornavirus antivirals can be with EV. The public-health challenge is always to find a used off-label or as part of outbreak control measures. balance between individual benefit and the long-term They may be used in the final stages of poliovirus eradi- health of the larger population. cation and to mitigate EV-A71 outbreaks. We review the Introduction Enteroviruses (EVs) are among the most common of the PV eradication process and as part of outbreak circulating viruses known. They are non-enveloped control measures when PV is eradicated [6]. Further- RNA viruses belonging to the large genus Enterovirus more, severe disease outbreaks with EV-A71 [7–9], may within the Picornaviridae family, which also includes be mitigated with EV antivirals, which are thus being human rhinoviruses (HRVs). In addition to poliovirus explored in Asia along with EV-A71 vaccine develop- (PV1–3, of the EV-C species), there are over 200 types ment [10,11]. of human non-polio enterovirus (NPEV) classified However, their effect on EV transmission and into four genetic species: EV-A to D (Table 1). Most endemic circulation are unknown, as is the potential EV infections remain asymptomatic or cause only mild for emergence and circulation of EV-resistant strains in gastrointestinal or respiratory disease in immunologi- the treatment-naive high-risk population. That poten- cally competent individuals. Severe disease manifes- tial is a major public-health concern in light of the anti- tations such as paralysis/poliomyelitis, meningitis, microbial resistance (AMR) caused by uncontrolled hand-foot-and-mouth disease (HFMD) and cardiac large-scale use of antimicrobial compounds in animal disease have been reported in immunocompetent per- production and the dissemination of these compounds sons but occur predominantly among infants, young into the environment [12–14]. The sheer magnitude of children and individuals with a humoral immune defi- these AMR strains circulating in the world population ciency. The development of antivirals to treat these has crippled antibiotic treatment options on a global high-risk patients has proceeded at a very rapid pace level. AMR has become a top priority for public-health over the past three decades [1–5]. institutes worldwide, with a strong focus on surveil- In addition to reducing pathology or disease duration lance of strains and monitoring drug usage. Critical for infected patients, antivirals can reduce virus excre- public-health scrutiny is required for EV antivirals as tion and shedding in the environment. These drugs are well, given their potential to be used on a large-scale being actively explored for use during the final stages basis, as an off-label drug, as part of outbreak control ©2015 International Medical Press 1359-6535 (print) 2040-2058 (online) 121 AVT-14-RV-3262_Benschop.indd 121 23/04/2015 09:58:15 KSM Benschop et al. Table 1. Classification of human enteroviruses into 4 genetic species EV-A EV-B EV-C EV-D Polioviruses – – 1–3 – Coxsackie A viruses 2–8, 10, 12, 14, 16 9 1, 11, 13, 15, 17–22, 24 – Coxsackie B viruses – 1–6 – – Echo viruses – 1–9, 11–21, 24–27, 29–34 – – EVs 71, 76, 89–92, 114, 119 69, 73–75, 77–88, 93, 97–98, 95–96, 99, 102, 104–105, 68, 70, 94, 111 101, 106–107 109, 113, 116–118 Adapted from van der Sanden et al. [98] with kind permission of Springer Science+Business Media. Numbers represent types. EV, enterovirus. measures or as an over-the-counter (OTC) medication. compound acts by preventing viral attachment through There is also the risk of dissemination of antiviral drugs deforming the receptor binding region [26]. Among the in the environment [15], with consequences unknown. capsid inhibitors developed for EVs, pleconaril, disoxaril, Of particular concern is that non-picornavirus- pirodavir, V-073 and BTA-798 have advanced into clini- directed drugs on the market, such as ribavirin (treatment cal trials (Table 2). of HCV infections [16]) and amantadine (treatment of Pleconaril was the first compound to exhibit a Parkinson’s disease [17] and previously influenza A virus broad-spectrum activity against EV and HRV. The infections [18]), have been shown to inhibit replication drug was clinically evaluated for treatment of the com- of PV and several NPEV types such as EV-A71, echovi- mon cold caused by HRV [27] and for compassion- rus (E)-5 and E-18 [19–24]. Thus the current and past ate use in patients with a potentially life-threatening use of these drugs in their target populations could be EV infection [28–30]. Clinical development was halted leading to circulation of drug-resistant EVs if targeted in 2002 due to inconsistent results in treating EV individuals are unknowingly coinfected with EV. infection and minimal clinical efficacy in treating the This review addresses the potential public-health HRV-associated common cold. Furthermore, plecon- implications of the use of antivirals against PV, NPEVs aril showed adverse effects [31]. The drug inhibits the and the related HRVs that have advanced into clinical cytochrome P-450 3A (CYP3A) enzyme activity [32], trials (Table 2). Furthermore, it explores the implica- leading to menstrual irregularities, and reduces the tions of the past and present use of licensed non-picor- efficacy of some hormonal contraceptives and anti- navirus-directed drugs that are also active against EVs. HIV drugs [31]. However, pleconaril was relicensed to Schering–Plough in 2003 and is being re-evaluated for Search strategies and selection criteria EV neonatal disease (clinicaltrial.gov NTC0031512) We searched Pubmed, with no date restriction, with the and for HRV-associated colds in high-risk patients terms: ‘antiviral(s)’; ‘antiviral(s)’ AND (‘enterovirus’ OR (clinicaltrial.gov NTC00394914; Table 2). ‘poliovirus’ OR ‘picornavirus’ OR ‘rhinovirus’ OR ‘influ- The capsid inhibitor V-073 (Viro-Defense, Atlanta, enza virus’ OR ‘HIV’); ‘antimicrobial/antibiotic’ AND GA, USA) is a potent in vitro inhibitor of PV replica- ‘resistance’; ‘antiviral(s)’ AND ‘resistance’; (‘antiviral(s)’ tion [33] has a good oral bioavailability and was well AND ‘resistance’) AND (‘transmission’ OR ‘circulation’ tolerated in mice [34]. OR ‘reatment-naïve’ or ‘public health’); ‘antiviral(s)’ It has therefore advanced into clinical trials aimed AND ‘recombination’; ‘recombination’ AND (‘enterovi- at PV eradication [6] (Table 2). The three other capsid rus’ OR ‘poliovirus’ OR ‘picornavirus’ OR ‘rhinovirus’). inhibitors, disoxaril, pirodavir and BTA-798 (vapen- For topics on drug resistance in the non-picornavirus davir; Biota Holdings, Notting Hill, Australia; Table 2) fields, we focused on the most recent comprehensive have until now been evaluated only for the treatment of reviews, but cite older reviews when appropriate. common cold caused by HRV. Disoxaril and pirodavir have failed to advance in clinical trials due to limited Antiviral compounds against enteroviruses clinical efficacy [35,36]. BTA-798 has completed the Phase II proof of concept in humans and was described Capsid inhibitors by Biota as achieving a significant reduction in severity of Capsid inhibitors are small compounds that can integrate community-acquired common cold in high-risk patients within the hydrophobic pocket of the capsid composed with asthma. by the outer capsid proteins, in particular VP3 and VP1 (Figure 1) [1]. Their integration leads to immobilization Protease inhibitors and compression of the capsid, whereby the virus is unable The protease inhibitors designed for picornaviruses are to release its RNA within the cell [25]. In some cases, the directed against the viral proteases 2A and 3C (Figure 1). 122 ©2015 International Medical Press AVT-14-RV-3262_Benschop.indd 122 23/04/2015 09:58:16 Antivirals against enteroviruses: a public-health perspective Table 2. Clinically evaluated compounds active against enteroviruses Drug Target Mode of action Treatment Clinical trial status Pleconaril Capsid Rigidification of pocket preventing RNA release Compassionate use for Compassionate use [30] life-threatening infections HRV common cold Phase III halted [31] HRV-induced exacerbation Phase II completed of asthma/COPD in high-risk NCT00394914 patients Neonatal sepsis Phase II ongoing NCT00031512
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