Mathematical models can be used to predict the emergence and transmission of antiviral resistance. Previously it has been predicted that high usage of antivirals (in immunocompetent populations) to treat Herpes Simplex Virus type 2 (HSV-2) would only lead to fairly low levels of antiviral resistance. The HSV-2 predictions were based upon the assumption that drug-resistant strains of HSV-2 would be less infectious than drug-sensitive strains but that the drug-resistant strains would not be impaired in their ability to reactivate. Recent data suggest that some drug-resistant strains of HSV-2 are likely to be impaired in their ability to reactivate. Objectives: (1) To predict the effect of a high usage of antivirals on the prevalence of drug-resistant HSV-2 under the assumption that drug-resistant strains will be less infectious than drug-sensitive strains of HSV-2 and also have an impaired ability to reactivate. (2) To compare predictions with previous published predictions.

We generated theoretical drug-resistant HSV-2 strains that were attenuated (in comparison with drug-sensitive strains) in both infectivity and ability to reactivate. We then used a transmission model to predict the emergence and transmission of drug-resistant HSV-2 in the immunocompetent population assuming a high usage of antivirals.

Our predictions are an order of magnitude lower than previous predictions; we predict that even after 25 years of high antiviral usage only 5 out of 10,000 immunocompetent individuals will be shedding drug-resistant virus. Furthermore, after 25 years, 52 cases of HSV-2 would have been prevented for each prevalent case of drug-resistant HSV-2.

The predicted levels of drug-resistant HSV-2 for the immunocompetent population are so low that it seems unlikely that cases of drug-resistant HSV-2 will be detected.

Mathematical models can be used as health policy tools to predict the emergence and transmission of antiviral resistance [

We used a previously published mathematical model to track the effect of a high usage of antivirals on the transmission dynamics of drug-sensitive and drug-resistant HSV-2 strains in an immunocompetent population [

To generate our predictions we analyzed the model using time-dependent uncertainty analyses [

We used sampling constraints during the LHS to construct 1,000 different drug-resistant HSV-2 strains that were attenuated in comparison with the drug-sensitive strains with respect to both infectivity and reactivation ability. The relationship β_{R }= αβ_{S }(where α was a random variable uniformly distributed between zero and one and β_{R }and β_{S }specified the infectivity (i.e., transmission probability) of drug-resistant and drug-sensitive strains respectively) was used to determine the infectivity level of drug-resistant strains. Attenuation in reactivation ability was derived in a similar manner by multiplying each of the 1,000 drug-sensitive reactivation rates (that had been obtained by LHS) by a randomly selected weighting factor (Η ; where 0 < Η < 0.25 with uniform pdf). Since most drug-resistant variants that have been studied are TK deficient and are attenuated both in infectivity and reactivation ability [

Biological attributes of the 1,000 strains of drug-resistant HSV-2 that were constructed using sampling constraints and LHS. Strains were generated to produce a strong positive correlation between the number of infectious episodes (N_{E}^{R}) and the transmissibility (β_{R}) of the drug-resistant strain. The correlation coefficient (r) of this data set is 0.83.

We then simulated the model and predicted the levels of drug resistance that would emerge, assuming that antiviral usage was high (i.e., that 10–50% of the individuals who were shedding virus at any particular time could receive episodic treatment). In order to compare with previous predictions we predicted the temporal dynamics of: (i) the prevalence of drug-resistant infectiousness and (ii) the value of the Treatment Evaluation Criterion (TEC(t)) where TEC(t) equals the average number of drug-sensitive cases prevented at time t per prevalent case of drug resistance [

The 1,000 theoretical drug-resistant strains of HSV-2 that we constructed were attenuated in both their infectivity and the ability to reactivate; sampling constraints ensured that infectivity and the average number of infectious episodes per year were positively correlated (Figure

Results of the uncertainty analyses using a previously published transmission model [

Previous estimates (blue data; Figure

Here we have predicted the emergence and transmission of antiviral resistance in the immunocompetent population (i.e., the "general population"). More complex models could be developed to assess the emergence and transmission of drug-resistant HSV-2 strains in a population that contains both immunocompetent and immunocompromised individuals. Acquired resistance occurs with a much greater probability in immunocompromised individuals (in comparison with imunocompetent individuals) due to a variety of host, virological and treatment factors [

Mathematical models can be very useful in predicting the spread of antiviral resistance [

None declared.

SMB conceived the study & designed the analysis, HBG performed the numerical computations. SMB & HBG drafted the manuscript. GD participated in the design, the interpretation of results, and drafting the manuscript. All authors read and approved the final manuscript.

The pre-publication history for this paper can be accessed here:

We thank the National Institute of Allergy & Infectious Diseases (Grant #: R01-AI41935 to SMB), and the Centers for Disease Control (Grant #: R18/CCR915950 to SMB) for financial support.