1. Effect of antiviral use on the emergence of resistance to nucleoside analogs in Herpes Simplex Virus, Type 1 Marc Lipsitch, Bruce Levin, Rustom Antia, Jeffry Leary, Teresa Bacon

2. Herpes Simplex Virus, Type 1 Cause of recurrent herpes labialis (RHL =“cold sores”) More severe diseases –Respiratory and neurologic infections –Neonatal herpes –Disseminated disease in immunocompromised patients

3. Impetus for work Topical antiviral Penciclovir, available Rx in US Sponsor wished to obtain OTC license FDA had denied OTC Acyclovir for genital herpes –Concerns about resistance, precedent Penciclovir sponsor requested resistance risk analysis

4. HSV-1 Transmission Primary asymptomatic or symptomatic infection, latency and reactivation Infection can be detected serologically Reactivation (cold sores) associated with heavy viral shedding 1-5% shedding among asymptomatic carriers Little direct evidence of when transmission occurs

5. HSV-1 Treatment and Resistance Nucleoside analog family –acyclovir (prodrug valacyclovir) –penciclovir (prodrug famciclovir) Prevents viral DNA replication Does not cure latently infected cells Resistance readily selected in vitro and in immunocompromised patients Resistance arises rarely in immunocompetent during treatment  virulence (usually), transmissibility (probably)

6. Resistance to nucleoside analogs in HSV-1 Presently about 0.3% in immunocompetent, 3- 10% in immunocompromised No evidence of increasing trend since acyclovir was introduced in early 1980s QUESTION: How would levels of resistance change following a substantial increase in nucleoside analog use? Research was sponsored by the manufacturer of topical penciclovir, which wished to apply for OTC status for the treatment of RHL

7. Cold Sores Untreated death Susceptible birth Seropositive: Sensitive Seropositive: Resistant Asymptomatic C.S. Treated Asymptomatic Cold Sores Basic Model for Transmission of Resistance Force of infection Force of infection

8. Complex Model I’ S S’ I’ R I’ D Immunocompetent Immunocompromised ISIS S infection IRIR birth IDID infection secondary infection Acquired resistance

9. Transmission of Resistance: Key Assumptions and Parameters Up to 30% of cold sore sufferers use topical PCV. Topical PCV reduces transmission of sensitive HSV-1. Individuals infectious when symptomatic, and possibly when asymptomatic. Resistance  transmissibility 0-50%. PCV treatment does not cause “acquired resistance.” Total or partial immunity to HSV-1 superinfection

10. Acyclovir Resistance in HSV-1: Model Predictions (No acquired resistance)

11. Acquired Resistance Approximately 1800 immunocompetent patients with multiple viral samples in clinical trials of nucleoside analogs (HSV-1 and HSV-2, oral and topical, several different compounds). No evidence of acquired resistance –0/1800 95%CI (0, 0.0017)  (0, 1/625) –Biological limitations of the assay Biological barriers 4 possible case reports in immunocompetent

12. Model with Acquired Resistance No acquired resistance P(AR) = 1/625 treated episodes P(AR) = 1/6250 treated episodes P(AR) = 1/2500 treated episodes

13. Conclusions: HSV-1 Very slow increase in prevalence of resistance from transmission alone Acquired resistance necessary for noticeable buildup of resistance, but the necessary rate of acquired resistance is extremely low (0.1% >>0) Moderate fitness cost of resistance can also markedly reduce rate of increase, even of acquired resistance Doubling times range from years to centuries Similar to predictions for HSV-2 (Blower et al.)

14. Conclusions Emergence rate a key determinant of outcome –Small, hard to measure Risk of resistance relatively low vs. other bug-drug combinations FDA advisory group recommended against approval –Antivirals adcom vs. OTC adcom

15. Lessons of the example Dynamic models required to estimate population process over time Both direct and indirect effects important Identified surprising locus of uncertainty Risk is only one side of the equation

16. What the model couldn’t do Calculate the probability of rare events (deterministic) Account for heterogeneities of resistant strains Be “validated” rigorously –Model predicted resistance would be low now –It is –So? These problems not unique to dynamical approach