Surveillance of herpes simplex virus resistance to antivirals: a 4-year survey.
Herpes simplex virus (HSV) resistance to antivirals constitutes a therapeutic challenge, especially among immunocompromised patients. This observational survey on HSV resistance to antivirals was conducted retrospectively over a 4-year period (2008-2012). A total of 211 HSV-positive clinical samples (94 HSV-1 and 117 HSV-2) recovered from 139 patients (11 immunocompetent patients, 85 immunocompromised patients, and 43 patients with unknown immune status) with suspected HSV drug-resistance were analyzed for acyclovir and foscarnet susceptibility. Antiviral resistance testing consisted in a two-step procedure including a first-step genotypic assay, based on UL23 (thymidine kinase, TK) and UL30 (Pol) gene sequencing, and a second-step phenotypic assay (i.e., plaque reduction assay) performed when unpreviously described mutations were detected. As a whole, susceptibility and resistance to antivirals were evidenced for 58 (30.7%) and 86 (45.5%) HSV, respectively, whereas antiviral profile remained undetermined for 45 (23.8%) HSV. The prevalence of drug resistance was significantly higher among HSV-2 isolates than among HSV-1 isolates (53.8% vs. 34.9%; p=0.012). The majority (i.e., 79.7%) of cases of ACV resistance conferred by TK mutations resulted from UL23 gene frameshift reading. Apart from the changes surely related to natural polymorphism or drug-resistance, 91 unpreviously reported mutations were identified in TK and Pol, including 51 potential natural polymorphisms, 22 mutations likely conferring resistance to antivirals, and 18 mutations of unclear significance.
UPMC Univ Paris 06, ER1 DETIV, Paris, France; Service de Virologie, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, AP-HP, Paris, France. Electronic address: sonia.burrel@psl.aphp.fr.
Sonia
S
Burrel
Catherine
C
Aime
Laurence
L
Hermet
Zaïna
Z
Ait-Arkoub
Henri
H
Agut
David
D
Boutolleau
D000212:Acyclovir / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D062665:Epidemiological Monitoring; D005260:Female; D017245:Foscarnet / Q000494:pharmacology*; D005838:Genotype; D006561:Herpes Simplex / Q000453:epidemiology / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D014764:Viral Proteins / Q000235:genetics; D055815:Young Adult
D000998:Antiviral Agents; D014764:Viral Proteins; D017245:Foscarnet; D000212:Acyclovir
DNA polymerase; HSV resistance to antivirals; Mutation database; Surveillance; Thymidine kinase