The six studies yielded a total of 5384 subjects whose baseline HSV-2 tests were negative and who were included in this pooled analysis. Four-hundred seventy five subjects were excluded because they reported no sex, or had no laboratory test or condom use interview during the follow up period (40 from the GSK valacyclovir study, 9 from the SKB vaccine study, 10 from the Chiron Partners study, 118 from the Chiron STD Clinic study, 38 from the Project RESPECT, and 260 from the Adolescent STD Incidence study). Overall, subjects had a mean age of 29, 66.2 percent were male, 60.4 percent were white, 94.1 percent were heterosexual, and most reported no prior STIs (). Sixty percent of the subjects were HSV-1 seropositive at study entry. The 5384 subjects contributed 2,040,894 follow-up days with a median follow withup of 374 days (range: 4, 987 days). Overall, 415 persons acquired laboratory-documented HSV-2 during follow-up. The overall incidence was 7.4 per 100 person years (95 percent confidence interval: 6.7, 8.2), but varied among studies (). Incidence was consistently higher for women than for men though the differences between genders varied greatly (). The study-specific median frequency of sex acts averaged 1.4 per week (range: 0.6, 1.9). The median number of partners reported during study was 1 (interquartile range: 1, 1.74) in the pooled data set and matched the study-specific median values except for the Adolescent STD Incidence Study (median: 2) and the Chiron vaccine STD Clinic study (median: 1.4). The median percent condom use during follow-up was lower in the studies that recruited discordant couples (7, 14 and 18 in Chiron vaccine Partners, SKB, and GSK valacyclovir, respectively) compared with other studies (from 46 to 53). In the pooled data, the median percent condom use was 39, and the subject averages over study follow-up had a u-shaped distribution () 44
. Variables univariately associated with HSV-2 acquisition included female gender, younger age, non-white race, and history of STIs ().
Characteristics of subjects included in the pooled analysis, by study and in the pooled dataset
HSV-2 incidence and 95 percent confidence intervals per 100 person years, by study and gender
Distribution of average percent condom use during study follow-up
Univariate associations with HSV-2 acquisition in the pooled analysis*
The association between a 25 percent increase in condom use and HSV-2 acquisition, adjusted for frequency of sex acts and stratified by study, indicated a weak protective effect that approached statistical significance (HR: 0.95; 95 percent confidence interval: 0.88, 1.00; P = 0.09). This effect did not significantly differ by gender (P = 0.22 for interaction).
In a multivariate model (), a 25 percent increase in condom use significantly decreased the risk of HSV-2 acquisition (HR: 0.93; 95 percent confidence interval: 0.85, 0.99; P = 0.01). Similarly, the aggregate hazard ratio for 100% condom use compared to 0% use was 0.70 (95 percent confidence interval: 0.40, 0.94; P = 0.01). No evidence of heterogeneity was found by study (P = 0.24) or gender (P = 0.22) in the adjusted model. In separate analyses for each study, increasing condom use was found to decrease the adjusted risk of HSV-2 acquisition; however, these estimates were only statistically significant for one study (). Baseline HSV-1 status, prior STI history, sexual orientation during study, and monogamy during study did not significantly predict HSV-2 acquisition during model selection and were not included in the final multivariate model.
Multivariate model of risk of HSV-2 acquisition, including condom effect and stratified on study
Study-specific hazard ratios (and 95 percent confidence intervals) for the effect of (a) a 25 percent increase in condom use and the effect of (b) increasing unprotected sex acts on HSV-2 acquisition
Secondary analysis of the effect of each additional unprotected sex act
In a univariate model stratified by study, the risk of HSV-2 acquisition increased significantly with increasing unprotected sex acts per week (0, 1, 2, 3,4 or more) (HR: 1.10; 95 percent confidence interval 1.02, 1.19; P=0.01). After adjustment for age, race, and gender, the estimate showed an increased risk of HSV-2 acquisition with increasing numbers of unprotected sex acts per week (HR: 1.16; 95 percent confidence interval: 1.08, 1.25; P<0.001) (). We observed no evidence for significant variation of this effect by gender (p = 0.41)). Overall estimates of the impact of the number of unprotected sex acts were also relatively consistent between study subgroups, except smaller effect was observed in the Project RESPECT and SKB vaccine subgroups (). However, an interaction between study and frequency of unprotected sex acts was not significant (P = 0.41).
Multivariate model of risk of HSV-2 acquisition, including unprotected sex act effect and stratified by study