Surveillance of herpes simplex virus resistance to antivirals: A 4-year survey

• Published in: Antiviral research Vol. 100; no. 2; pp. 365 - 372
• Main Authors: Burrel, Sonia, Aime, Catherine, Hermet, Laurence, Ait-Arkoub, Zaïna, Agut, Henri, Boutolleau, David
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.11.2013; Elsevier
• Subjects: Acyclovir - pharmacology; Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - pharmacology; Biological and medical sciences; Child; Child, Preschool; DNA polymerase; Drug Resistance, Viral; Epidemiological Monitoring; Female; Foscarnet - pharmacology; Genotype; Herpes Simplex - epidemiology; Herpes Simplex - virology; Herpes simplex virus 1; Herpes simplex virus 2; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - isolation & purification; Herpesvirus 2, Human - drug effects; Herpesvirus 2, Human - genetics; Herpesvirus 2, Human - isolation & purification; HSV resistance to antivirals; Humans; Male; Medical sciences; Microbial Sensitivity Tests; Middle Aged; Mutation database; Pharmacology. Drug treatments; Prevalence; Retrospective Studies; Surveillance; Thymidine kinase; Viral Proteins - genetics; Young Adult; Mutation database; HSV resistance to antivirals; Thymidine kinase; Surveillance; DNA polymerase; Enzyme; Herpesviridae; Transferases; Alphaherpesvirinae; Virus; Resistance; Nucleotidyltransferases; Survey; Database; Antiviral; Herpesvirus hominis; Mutation; DNA-directed DNA polymerase
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2013.09.012

•Observational retrospective 4-year survey of HSV resistance to antivirals.•Numerous novel mutations accounting for natural polymorphism or drug-resistance.•Useful data for a database on HSV genotypic resistance to antiviral. 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.