Effects of Antiviral Usage on Transmission Dynamics of Herpes Simplex Virus Type 1 and on Antiviral Resistance: Predictions of Mathematical Models

Abstract

Herpes simplex virus type 1 (HSV-1) causes recurrent herpes labialis (RHL), a common disease afflicting up to 40% of adults worldwide. Mathematical models are used to analyze the effect of antiviral treatment on the transmission of, and the prevalence of drug resistance in, HSV-1 in the United States. Three scenarios are analyzed: no antiviral use, the current level of use, and a substantial increase in nucleoside analogue use, such as might occur if topical penciclovir were available over-the-counter for the treatment of RHL. A basic model predicts that present level of nucleoside analogue use has a negligible effect on HSV-1 transmission and that even if use of topical penciclovir for (RHL) increased substantially, the overall prevalence of infectious HSV-1 is unlikely to be reduced by more than 5%. An expanded model, which allows for acquired resistance and includes immunocompromised hosts and other more realistic features, predicts that current antiviral use is unlikely to lead to any noticeable increase in resistance. If antiviral use increases, the resulting rise in resistance in the population will depend primarily on the probability that immunocompetent hosts will acquire permanent resistance upon treatment. This probability is known to be small, but its exact value remains uncertain. If acquired resistance occurs less than once per 2,500 treated episodes, then in the community at large, the frequency of HSV-1 resistance is predicted to increase slowly, if at all (remaining below 0.5% for >50 years), even with extensive nucleoside analogue use. If acquired resistance emerges in 1 of 625 treated episodes (the maximum of an approximate 95% confidence interval derived from the results of several studies of resistance in treated hosts), then the prevalence of infection with resistant HSV-1 could rise from about 0.2% to 1.5 to 3% within 50 years. The limitations of existing data on acquired resistance and the potential impact of acquired resistance if it occurs are discussed, and strategies are suggested for enhancing information on acquired resistance. The predictions of this model contrast with the more rapid increases in antimicrobial resistance anticipated by models and observed for other pathogenic bacteria and viruses. The reasons for these contrasting predictions are discussed.

Inhibition of Cyclooxygenase 2 Synthesis SuppressesHerpes simplexVirus Type 1 Reactivation

“…However, differences of less or comparable magnitude are regarded as both biologically and clinically significant in a variety of clinical studies of new antiviral drugs against herpes. 10,11,[39][40][41][42][43][44][45] Thus, the difference between 23% reactivation in COX-2-treated mice compared to 54% in control, untreated mice seen in our study is biologically and likely clinically significant if translated to humans. It may be that a combination of an antiviral drug, such as acyclovir, and celecoxib, a COX-2 inhibitor, would either additively or synergistically enhance the level of inhibition of viral reactivation.…”

Herpes Simplex Virus Resistance to Acyclovir and Penciclovir after Two Decades of Antiviral Therapy

“…Another model was developed to predict the effect of topical antiviral use by individuals with recurrent herpes labialis on the transmission and prevalence of resistant HSV-1 (46). Even a substantial increase in the antiviral treatment of recurrent herpes labialis (episodic), such that 30% of all recurrences were treated with penciclovir, was calculated to have a minimal effect on the prevalence of HSV-1 infection in the community.…”

How Do Measurements of Antibiotic Consumption Relate to Antibiotic Resistance?

“…Mathematical modeling of relationships between antimicrobial use and resistance and the relative contribution of infection control measures has greatly enhanced our understanding of the complexity of the relationships. (Austin and Anderson, 1999;Austin et al, 1999b;Levin et al, 1997;Lipsitch et al, 2000b;Lipsitch and Samore, 2002).…”