Infectious Diseases in Obstetrics and Gynecology 5 70 60 ) (%50 g n i dd40 e h s ith30 w say 20 D 10 0 70 ) (%60 g n i dd50 e h s la 40 c i n licb30 u s ith20 w say 10 D 0 A B HSV 2+ (a) HSV − HSV 2− HSV 2+ (b) HSV − HSV 2− Figure 1: Scatter plot of shedding data for subjects receiving placebo in the ﬁrst treatment period. The column labeled HSV-2 + shows data from subjects whose HSV-2 antibody test was positive at enrollment (n = 31). The horizontal line represents the mean value. The next column shows the individual values for the 3 subjects who were negative for both HSV-1 and HSV-2 antibody; the next column shows the one subject who was HSV-1 antibody positive and HSV2 antibody negative at enrollment. (a) Total HSV-2 shedding, and (b) subclinical shedding. 4. Discussion The present study is the ﬁrst to evaluate valacyclovir 1 g once daily to reduce HSV-2 viral shedding in a population of subjects newly diagnosed with genital herpes infection. In our study, valacyclovir 1 g once daily signiﬁcantly reduced viral shedding by 78% compared to placebo. The eﬀect of suppressive valacyclovir therapy on reducing viral shedding and reducing the frequency of genital recurrences is similar to that reported in earlier studies that enrolled persons with an established history of genital herpes [12, 13, 18, 19]. Results from a large, randomized, controlled study demonstrated that valacyclovir suppression (500 mg daily) reduced transmission of symptomatic HSV2 infection by 75% and overall acquisition (HSV-2 seroconversion) by 48% in discordant couples [12]. Within this trial, a viral shedding substudy of 89 patients evaluated for 60 days demonstrated a 73% reduction in total days of viral shedding (mean 2.9% versus 10.8%, as measured by PCR) and a 64% reduction in days of subclinical viral shedding (mean 2.8% versus 7.8%) in infected source partners receiving valacyclovir compared to those receiving placebo. In a study of valacyclovir 1 g once daily for the reduction of HSV-2 viral shedding in 152 subjects with a history of ≥6 genital herpes recurrences per year, the mean percent of days with HSV-2 shedding was 9.3% in the placebo group and 2.7% in the valacyclovir group, a 71% reduction (P < .001). The mean percent of subclinical days with shedding was 6.4% on placebo and 2.7% in the valacyclovir group, a 58% reduction (P < .001) [13]. In another HSV-2 viral shedding study that enrolled a heterogeneous population of 69 subjects (newly diagnosed with HSV-2 infection, and diagnosed >6 months prior to study entry), participants received oral valacyclovir 500 mg BID, acyclovir 400 mg BID, and placebo in random order for 7 weeks each, in a three-period crossover design [11]. There was a one-week washout between treatment periods. However, 27 subjects (39%) had a diagnosis of a ﬁrst episode of genital herpes ≤6 months before randomization. Overall, for the 69 subjects randomized, HSV DNA was detected by PCR from at least one anatomical site on 40.2% of the days while receiving placebo, compared to 8.0% of days while receiving acyclovir (80% reduction) and 7.2% of days while receiving valacyclovir (82% reduction). In the current study, the mean percent of days with total HSV-2 shedding was 2.9% while receiving valacyclovir, compared to 13.5% while receiving placebo. These results are similar to those of the ﬁrst two studies [12, 13] noted above except that the proportion of days with shedding while on placebo was slightly higher in the current study. It is not clear if that diﬀerence is meaningful, but it could be because our subjects were recently infected and these persons shed virus more frequently than those with established disease [8, 9]. The study by Gupta et al. reported rates of shedding in both the placebo and treatment phases that were higher than those of the current study. However, the proportional reduction of shedding in subjects on suppression in our study was similar to that reported by Gupta et al. The reason for the discrepancy between the results reported by Gupta et al. and other studies, including the one reported here, is uncertain, but could be related to the multiple swab technique used in the earlier study or in the selection of study subjects [11]. Of the 70 subjects in this study, 9 (13%) were HSV- 2 seronegative at the time of diagnosis by culture or PCR. These subjects clearly had new HSV-2 infections while the remaining study subjects had been infected long enough to mount an antibody response by the time they enrolled in the study. This provided us with the opportunity to explore the diﬀerences in viral shedding between those with and without antibodies to HSV-2 in the group ran- domized to placebo treatment in the ﬁrst study period. As was previously reported in a study that evaluated viral shedding by culture in initially HSV-2 seronegative subjects [23], asymptomatic shedding was extremely common. Our