Resistance of herpes simplex viruses to acyclovir: An update from a ten-year survey in France Emilie Frobert a,b,⇑ , Sonia Burrel c,d , Sophie Ducastelle-Lepretre e , Geneviève Billaud a , Florence Ader f , Jean-Sébastien Casalegno a,b , Viviane Nave a , David Boutolleau c,d , Mauricette Michallet e , Bruno Lina a,b , Florence Morfin a,b a Laboratoire de Virologie, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France b Virologie et Pathologie Humaine, Université Lyon 1, EA 4610, Faculté de Médecine RTH Laënnec, Lyon, France c Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), INSERM U1135, Paris, France d AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière – Charles Foix, Service de Virologie, Paris, France e Service d’Hématologie Clinique, Centre Hospitalier Lyon Sud, Lyon, France f Service de Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse, Lyon, France article info Article history: Received 1 July 2014 Revised 30 July 2014 Accepted 25 August 2014 Available online 8 September 2014 Keywords: Herpes simplex virus Survey Antiviral drug resistance Hematopoietic stem cell transplant patients UL23 thymidine kinase UL30 DNA polymerase abstract The widespread use of acyclovir (ACV) and the increasing number of immunocompromised patients have raised concern about an increase in ACV-resistant herpes simplex virus (HSV). ACV resistance has tradi- tionally been a major concern for immunocompromised patients with a frequency reported between 2.5% and 10%. The aim of this study was to reassess the status of HSV resistance to ACV in immunocompetent and immunocompromised patients over a ten year period, between 2002 and 2011. This was done by ret- rospectively following 1425 patients. In immunocompetent patients, prevalence of resistance did not exceed 0.5% during the study period; whereas in immunocompromised patients, a significant increase was observed, rising from 3.8% between 2002 and 2006 (7/182 patients) to 15.7% between 2007 and 2011 (28/178) (p = 0.0001). This sharp rise in resistance may largely be represented by allogeneic hema- topoietic stem cell transplant patients, in which the prevalence of ACV resistance rose similarly from 14.3% (4/28) between 2002 and 2006 to 46.5% (26/56) between 2007 and 2011 (p = 0.005). No increase in ACV resistance was detected in association with other types of immune deficiencies. Genotypic char- acterization of HSV UL23 thymidine kinase and UL30 DNA polymerase genes revealed 11 and 7 previously unreported substitutions, respectively. These substitutions may be related to potential polymorphisms, drug resistance, or other mutations of unclear significance. Ó 2014 Elsevier B.V. All rights reserved. 1. Introduction Repeated and long-term acyclovir (ACV) use associated with clinical and immunological features may lead to the development of herpes simplex virus (HSV) resistant to this drug. HSV resistance to ACV is primarily a concern for immunocompromised patients whereas the prevalence remains low in immunocompetent patients. Since the commercialisation of ACV in the 1980s, resis- tance to this drug in immunocompetent patients has been esti- mated at 0.5% (Christophers et al., 1998; Fife et al., 1994; Nugier et al., 1992). After twenty years of use, the prevalence did not increase (Danve-Szatanek et al., 2004; Stranska et al., 2005). Never- theless, the recurrent and widespread use of ACV and its prodrug Val-ACV, including FDA-approved short-course and high dose reg- imens to treat HSV recurrence, may be contributing factors towards the emergence of resistance (Cunningham et al., 2012). One recent Chinese study reported an unexpectedly high preva- lence of ACV-resistant HSV of 4% in immunocompetent children with oral herpetic lesions (Wang et al., 2011). Further, some cases of recurrent herpetic keratitis have been found to be associated with ACV-resistant virus with a prevalence of 6.4% in immunocom- petent patients (Duan et al., 2009). Additionally, immunocompe- tent patients with genital herpes have a higher prevalence of ACV-resistant HSV (Kriesel et al., 2005). With regards to immuno- compromised patients, the prevalence of ACV-resistant HSV is lar- gely higher and varies between 3.5% and 10%, depending on the type of immunosuppression. HSV resistant to ACV can induce large, http://dx.doi.org/10.1016/j.antiviral.2014.08.013 0166-3542/Ó 2014 Elsevier B.V. All rights reserved. ⇑ Corresponding author at: Laboratoire de Virologie, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, 59 boulevard Pinel, 69 500 Bron, France. Tel.: +33 4 72 12 96 53; fax: +33 4 72 12 95 00. E-mail address: emilie.frobert@chu-lyon.fr (E. Frobert). Antiviral Research 111 (2014) 36–41 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral