Antiviral susceptibilities of herpes simplex virus from immunocompetent subjects with recurrent herpes labialie: a UK-based survey

R. J. Boona,*, T. H. Bacona, H. L. Robeya, T. J. Colemana, A Connollyb, P. Crossonc and S. L. Sacksc,d

a SmithKline Beecham Consumer Healthcare, St George's Avenue, Weybridge, Surrey KT14 0DE; b The Ridge Medical Practice, Great Horton, Bradford, Yorkshire BD7 3EE for and on behalf of Profiad Ltd, 20-24 Vachel Road, Reading RG1 1NY, UK; c Viridae Clinical Sciences, Inc., 1134 Burrard Street, Vancouver, BC V6Z 1Y8, Canada; d Department of Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada

Sir,

Use of penciclovir and acyclovir and their respective oral prodrugs to treat herpesvirus infections has increased dramatically since the introduction of acyclovir almost 20 years ago. Nevertheless, the prevalence of acyclovirresistant herpes simplex virus (HSV) remains exceedingly low and unchanged in immunocompetent hosts.14 Surveys of resistance have predominantly focused on HSV isolates from genital sites, despite use of topical antivirals for recurrent herpes labialis (RHL). To address this need, we report the results from a survey of RHL isolates conducted in the UK during 1998. If antiviral treatment in the immunocompetent host were to lead to the emergence of resistance, the UK is of particular relevance, since at the time of the survey, topical acyclovir had been available for 14 years, including 5 years over-the-counter (OTC), and topical penciclovir on prescription for 2.5 years.

Subjects were recruited across the UK by 54 general practitioners and at two clinical research institutions. Swabs were taken from 1304 immunocompetent subjects (aged >=18 years) with an untreated episode of RHL at the vesiculoulcerative stage, to enable the susceptibility of naïve, reactivated virus to be assessed. Virus was isolated and typed by standard methods, and susceptibilities to acyclovir and penciclovir were measured by plaque reduction assay in Vero and MRC-5 cells, respectively. Because cell type affects absolute antiviral activity, comparisons of the susceptibility data between these two compounds are inappropriate.

From 1297 swabs, 924 HSV isolates were obtained (isolation rate = 71.2%). Almost all were HSV-1 (99.6%; 920/924): two HSV-2 isolates were identified and two isolates were of mixed type (HSV-1/HSV-2).

The in vitro breakpoint for resistance to acyclovir was an IC50 (50% inhibitory concentration) >=2.0 mg/L based on the correlation between clinical resistance to acyclovir and in vitro IOC50.5 For penciclovir, an IC50 >= 2.0 mg/L or >=3x mean IC50 of penciclovir for all survey isolates tested (1.93 mg/L) was defined as resistant.

One resistant isolate was identified. This isolate was resistant to both acyclovir and penciclovir to give a prevalence of 0.11% (acyclovir: 1/924; 95% CI of 0.00–0.60%; penciclovir: 1/915; 95% CI of 0.00–0.61%) in this population (TableGo). IC50 was 11 mg/L and 219 mg/L, respectively. The resistant isolate was a thymidine kinase (TK)–negative HSV-1 mutant, which encoded a truncated TK gene product (R. T. Sarisky, SB Pharmaceuticals, personal communication). The isolate was from a 33-year-old Caucasian female, who reported a 25-year history of RHL, including 10 episodes in the previous 12 months, and prior use of topical antivirals for RHL (data on frequency of use as not collected). The subject's history of RHL was not unusual in that 23% of virus-positive subjects (217/924) reported a history of RHL for >16 years, four or more episodes in the previous 12 months, and prior use of topical antivirals.


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Table. Susceptibility of HSV isolates from subjects with recurrent herpes labialis as measured by the plaque reduction assaya
 
Median IC50s were compared across subgroups (TableGo). Previous use of topical antivirals for RHL was common (79%), but had no impact on susceptibility to either compound (acyclovir, P = 0.160; penciclovir, P = 0.955). Similarly, isolates from subjects reporting frequent episodes of RHL (four or more episodes/year) were equally sensitive to isolates from those with less frequent episodes. Duration of RHL did not affect susceptibilities of HSV isolates to either compound.

In summary, the prevalence of acyclovir- or penciclovir-resistant HSV among immunocompetent subjects with RHL was very low (0.1%) despite widespread OTC availability of topical acyclovir in the UK. This result is consistent with surveillance data for acyclovir-resistant HSV in the immunocompetent population (prevalence = 0.1– 0.6%) but remains considerably below 6%, the prevalence typically reported for immunocompromised patients.14 The low risk of resistance in the setting of competent immunity is likely to reflect effective viral clearance. There is no evidence that topical antiviral therapy for RHL, even with OTC availability, is affecting the prevalence of resistance.

Acknowledgments

The authors wish to thank S. Modin for statistical analyses, and J. J. Leary and R. T. Sarisky for scientific advice.

Notes

J Antimicrob Chemother 2000;46: 324–325

* Corresponding author. Tel: +44-1032-822-039; Fax: +44-1932-822-035 E-mail: ron.j.boon{at}sb.com Back

References

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