Resistance of herpes simplex viruses to acyclovir: An update from a ten-year survey in France

Highlights

• In immunocompetent patients, HSV resistance to ACV has not increased.

• In immunocompromised patients, HSV resistance to ACV increased significantly from 3.8% in 2002–2006 to 15.7% in 2007–2011.

• The increase was represented by HSCT patients, wherein the prevalence rose from 14.3% in 2002–2006 to 46.5% in 2007–2011.

• Resistance in other types of immune deficiencies did not increase.

• 11 and 7 previously unreported substitutions were characterized in the UL23 and UL30 genes, respectively.

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 traditionally 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 retrospectively 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 hematopoietic 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 characterization 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.

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, resistance to this drug in immunocompetent patients has been estimated 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). Nevertheless, the recurrent and widespread use of ACV and its prodrug Val-ACV, including FDA-approved short-course and high dose regimens 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 prevalence 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 immunocompetent patients (Duan et al., 2009). Additionally, immunocompetent patients with genital herpes have a higher prevalence of ACV-resistant HSV (Kriesel et al., 2005). With regards to immunocompromised patients, the prevalence of ACV-resistant HSV is largely higher and varies between 3.5% and 10%, depending on the type of immunosuppression. HSV resistant to ACV can induce large, extensive and ulcerative cutaneous infections, but also esophagitis, pneumonia and encephalitis, which can be fatal without clinical improvement. Among immunocompromised patients, the prevalence of resistance was reported between 3.5% and 7% in HIV patients, 2.5% and 10% in solid organ transplant patients, and with the greatest prevalence witnessed at 4.1% and 10.9% in hematopoietic stem cell transplant (HSCT) patients (Danve-Szatanek et al., 2004, Piret and Boivin, 2011). The prevalence has even been observed as high as 25% in allogeneic HSCT patients (Chakrabarti et al., 2000, Morfin et al., 2004).

95% of resistant cases are attributed to mutations on the UL23 gene encoding for thymidine kinase and 5% are attributed to mutations on the UL30 gene encoding for viral DNA polymerase (Piret and Boivin, 2011, Piret and Boivin, 2014). Antiviral drug resistance screening using genotypic techniques are an efficient approach to make prompt virological detection to adapt antiviral treatment. Nevertheless, genotypic characterization of UL23 and UL30 genes have revealed many natural polymorphisms in both genes, which can complicate the interpretation of genetic sequences, particularly when detected substitutions have not been previously described or characterized (Burrel et al., 2010).

The objectives of the present study were: (i) to reassess the frequency of ACV resistance in immunocompetent and immunocompromised patients from a ten-year survey; (ii) to describe new potential polymorphisms and resistance mutations, in the UL23 and UL30 genes, based on 22 ACV-sensitive and 40 ACV-resistant HSV.