1. 1 Suppressive Valacyclovir Therapy Soon After Initial Genital Herpes: Clinical Efficacy and Impact on Herpes-Related Quality of Life Hunter Handsfield Terri Warren Victory Murphy Mica Werner University of Washington and Public Health - Seattle & King County, Seattle, WA Westover Heights Clinic, Portland, OR

2. 2 Early Suppressive Therapy for Genital Herpes Rationale Genital herpes is the most prevalent STD in the US It is the one of greatest concern to sexually active people in the US behind HIV/AIDS The need for suppressive therapy may be greatest in the first 6-12 months after acquisition when: Outbreaks most common Most viral shedding Most psychological distress But suppression has been studied in persons with genital herpes a year or more in duration

3. 3 To determine the efficacy of suppressive treatment with valacyclovir initiated very early in the course of infection Endpoints: - No. of symptomatic recurrences - Number of patients recurrence free during follow-up - Psychological effect of genital herpes Early Suppressive Therapy for Genital Herpes Purpose

4. 4 Study Design Double-blind, placebo-controlled, randomized trial Heterosexual men and women HIV negative by history Clinical diagnosis of first episode genital herpes within 60 days prior to enrollment or within 120 days of first diagnosis and within 60 days of first recurrence

5. 5 Study Design Laboratory tests - HSV culture and/or PCR of lesions - Glycoprotein G-based serology for HSV-1 and HSV- 2 at enrollment; follow-up serology if initial PCR or culture negative First episode treatment given for 10 days, if indicated Then valacyclovir 1 g or placebo QD for 6 months Recurrences treated with open-label valacyclovir 500 mg bid for 5 days; study drug withheld during this

6. 6 Study Design Follow-up - Clinic visits at enrollment, 1 mo, 3 mo, 6 mo and for first suspected recurrent outbreak - Telephone follow-up 2 wk, 2 mo, 4 mo, 5 mo First recurrence assessed in person, subsequent outbreaks reported by telephone Herpes-related psychological impact evaluated at baseline, 3 mo and 6 mo

7. 7 Herpes Related Psychological Impact Assessment (HRPIA) Previously known as Herpes Related Quality of Life Self-administered, 5-6 min 20 items, Likert scale (0-3 points) Minimum score 0, maximum 60 Subject areas - Self-esteem - Social functioning - Sexual functioning - Personal relationships - Mental health

8. 8 Herpes Related Psychological Impact Assessment: Sample Items Herpes affects my self confidence Herpes is affecting my sex life I get depressed about having herpes Herpes makes makes it difficult to plan ahead Very much Quite a bit A little Not at all 01230123 Higher score is better and rise in score indicates improvement

9. 9 Intent to treat (ITT), regardless of diagnostic confirmation - HSV-2 - HSV-1 - HSV, type unknown - HSV not documented Separate analysis of cases with documented HSV-2 infection Data Analysis N 75 22 2 20

10. 10 Study Population Age, yr, mean + SD Female, No. (%) White, No. (%) New partner 2 mo, No. (%) HSV diagnosis, No. (%) - HSV-2 - HSV-1 - HSV, type unknown - HSV unconfirmed HRPIA score, mean + SD Followed >3 mo, No. (%) 28.5 + 8.9 35 (58) 49 (82) 29 (48) 38 (63) 9 (15) 1 (2) 12 (20) 28.6 + 14.6 44 (73) 29.0 + 8.8 43 (73) 47 (80) 20 (34) 37 (63) 13 (22) 1 (2) 8 (14) 31.2 + 14.8 44 (75) Valacyclovir N=60 Placebo N=59

11. 11 Recurrent Herpes Outbreaks During Follow- up: ITT Analysis Outbreak-free, No. (%) Number of outbreaks Mean + SD Median Range 35 (58) 0.7 + 1.0 0 0 - 5 19 (32) 1.6 + 2.0 1 0 - 11 0.006 0.004 Valacyclovir N=60 Placebo N=59 P

12. 12 Recurrent Herpes Outbreaks During Follow- up: ITT Analysis No. of Outbreaks 35 19 15 21 7 6 3 13 0 10 20 30 40 50 60 012>3>3 Valacyclovir Placebo Percent of Patients Bars display no. of subjects P = 0.004

13. 13 Recurrent Herpes Outbreaks During Follow-up: Confirmed HSV-2 Outbreak- free, No. (%) Number of outbreaks Mean + SD Median Range 18 (47) 0.9 + 1.2 1 0 - 5 10 (27) 2.0 + 2.4 1 1 - 11 0.095 0.011 Valacyclovir N=38 Placebo N=37 P

14. 14 Recurrent Herpes Outbreaks During Follow- up: Confirmed HSV-2 No. of Outbreaks 18 10 9 6 5 3 12 0 10 20 30 40 50 60 012>3>3 Valacyclovir Placebo Percent of Patients Bars display no. of subjects P = 0.012

15. 15 Herpes-Related Psychological Impact Assessment: ITT Analysis Baseline 3 mo 6 mo 56 45 43 28.6 + 14.6 43.7 + 10.1 45.5 + 10.5 Valacyclovir 31.2 + 14.8 41.1 + 13.9 40.1 + 14.6 0.36 0.33 0.05 Placebo P Score, Mean + SD 55 47 43 N N

16. 16 Herpes-Related Psychological Impact Assessment: ITT Analysis 0 3 mo 0 6 mo 42 40 14.1 + 12.5 15.5 + 15.0 N Valacyclovir 10.1 + 8.9 9.7 + 11.1 0.10 0.052 Placebo P Change in HRPIA Score, Mean + SD 45 41 N

17. 17 Herpes-Related Psychological Impact Assessment: Confirmed HSV-2 Baseline 3 mo 6 mo 34 30 28 26.6 + 14.6 42.1 + 10.5 43.4 + 11.3 Valacyclovir 34.4 + 15.2 42.8 + 13.6 38.8 + 14.1 0.034 0.83 0.18 Placebo P Score, Mean + SD 36 32 30 NN

18. 18 Herpes-Related Psychological Impact Assessment: Confirmed HSV-2 0 3 mo 0 6 mo 27 25 14.0 + 13.4 14.6 + 16.4 N Valacyclovir 8.0 + 6.9 6.1 + 9.1 0.039 0.023 Placebo P Change in HRPIA Score, Mean + SD 30 28 N

19. 19 Early Suppressive Therapy for Genital Herpes Summary Suppressive therapy with valacyclovir given within 60-120 days after acquisition of genital herpes is superior to placebo in:  Reducing the # of symptomatic recurrent outbreaks  Ameliorating psychological impact Suppression may be less effective in preventing symptomatic recurrences in early herpes than in infections >1 year duration

20. 20 Early Suppressive Therapy for Genital Herpes Limitations Small trial with limited statistical power All except the first recurrent outbreaks were self-diagnosed by the patients which may be hypervigilance in newly diagnosed patients rather than actual outbreaks Recurrence rates have not yet been adjusted for duration of follow-up (I.e. some followed shorter time periods, some longer No data on subclinical shedding or transmission

21. 21 Early Suppressive Therapy for Genital Herpes Conclusions Early valacyclovir suppressive therapy is effective in reducing recurrences and improving psychological adjustment Further study is needed to confirm and extend these pilot results (Planning underway for a multicenter RCT) The present results support such therapy for selected patients. Counsel patients that their partners may not be protected from transmission even while on suppression.

22. 22 Early Suppressive Therapy for Genital Herpes Acknowledgments Bob Deeter, formerly of GlaxoSmithKline Jennifer Almekinder, GlaxoSmithKline Jim Phillips, Sage Statistical Solutions Westover Heights Clinic staff Public Health - Seattle & King County STD Clinic staff The patients who served and the providers who referred them