Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization.
BACKGROUND
Widespread and frequent use of acyclovir (ACV) for treatment, suppressive therapy and prophylaxis of herpes simplex virus (HSV) infections and its over the counter availability may be associated with emergence of HSV resistance.


OBJECTIVE
To determine the prevalence of ACV-resistant HSV isolates in different patient groups between 1999 and 2002 in the Netherlands.


METHODS
A total of 542 isolates, 410 HSV-1 and 132 HSV-2, from 496 patients were screened for reduced susceptibility to ACV. A newly developed ELVIRA HSV screening assay was used that allowed a high throughput screening. The genotypic analysis of the HSV thymidine kinase gene was performed to identify resistance-associated mutations.


RESULTS
Thirteen isolates, 8 HSV-1 and 5 HSV-2, from 10 patients (2%) were found resistant to ACV. A single ACV-resistant strain was identified among isolates from 368 immunocompetent patients (0.27%; 95% confidence interval [CI], 0.007%-1.5%), whereas in nine isolates from 128 immunocompromised patients resistant HSV was identified (7%; 95% CI, 3.26%-12.93%). The highest frequency of ACV-resistant HSV was associated with bone marrow transplantation: four patients out of 28 (14.3%) shed resistant virus. In addition, resistant virus was obtained from two HIV-positive patients, one patient with a hematological malignancy and two patients on immunosuppressive drugs. Further testing showed that none of the isolates was resistant to foscarnet. Several new mutations were identified in the thymidine kinase gene of these resistant isolates, and their effect on ACV-resistance is discussed.


CONCLUSIONS
Our study shows that the prevalence of ACV resistance is low in immunocompetent patients (0.27%), whereas ACV-resistant HSV infections occur relatively frequently in immunocompromised patients (7%; P < 0.0001). This emphasizes the need for drug susceptibility monitoring of HSV infections in immunocompromised patients with persisting infections despite antiviral therapy.
Stránská
Růzena
R
Department of Virology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. r.stranska@lab.azu.nl
Schuurman
Rob
R
Nienhuis
Elske
E
Goedegebuure
Irma W
IW
Polman
Merjo
M
Weel
Jan F
JF
Wertheim-Van Dillen
Pauline M
PM
Berkhout
Ron J M
RJ
van Loon
Anton M
AM
D000212:Acyclovir / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D024882:Drug Resistance, Viral; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D007121:Immunocompetence; D008297:Male; D008826:Microbial Sensitivity Tests; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D018139:Simplexvirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics
D000212:Acyclovir