The current HSV 2 antibody test was positive in 43 participants (33.9%, 95% confidence interval [CI] 25.6–42.1) in the overall population and in 41 of those for whom we have current behavioral information (Table 1). Only 4 participants were aware that they were HSV 2 positive (2 with symptomatic genital herpes and 2 with a known positive antibody test but no symptoms) before the current test. All participants were given the results of their HSV 2 antibody test, usually at their next quarterly visit. Univariate logistic regression models were used to identify factors associated with a positive HSV 2 antibody test (Table 1). Women who were older, had an earlier sexual debut, and had a larger number of lifetime sexual partners were more likely to have a positive HSV 2 antibody test. The frequency of genital symptoms (pain or discharge) in the 270 days before the test was not associated with the presence of HSV 2 antibody nor was a history of sexually transmitted infections. In a multivariate analysis, none of the factors identified in the univariate analysis was independently associated with a positive HSV 2 antibody test.
The 43 participants who were HSV 2 antibody positive had one set of available weekly vaginal swabs tested for HSV 2 DNA to evaluate viral shedding (see Methods for details about how these specimens were selected). A total of 32 of the 43 HSV 2 antibody positive participants (74.4%; 95% CI, 61.4%–87.5%) had HSV 2 DNA detected on at least one swab from the collection period selected. The patterns of HSV 2 shedding are shown in Table 3 for the participants who shed virus at least once. Overall, HSV 2 shedding was documented on 73 of 539 specimens tested (13.6%); among the 32 participants who had at least one positive swab specimen, 73 of 397 specimens (18.4%) were positive.
During the diary periods, participants recorded whether they experienced vaginal pain and whether they had a vaginal discharge each day. These symptoms were subjectively defined by the participants; they were not given guidance or definitions for these symptoms. No other symptoms (such as itching or genital lesions) were recorded in the diaries. For participants who had shedding of HSV 2 DNA detected on a genital swab, we evaluated the presence of genital symptoms on the day that shedding was detected or in a window that extended from 1 day before to 1 day after the swab was collected. The odds ratio for shedding of HSV 2 DNA was 2.0 (95% CI, 1.1–3.6, P = 0.02) if there was pain recorded in the 3-day window around the time of the swab. There was no association between the presence of vaginal discharge and detection of HSV 2 DNA. Although there was a statistically significant association between genital pain and HSV 2 shedding, the sensitivity of pain as a predictor of shedding was low (4/73 or 5.5%) and the positive predictive value was only 23.5%. The days when symptoms were associated with HSV 2 DNA shedding are shown in Table 3.
Despite the apparent recent decline in HSV 2 seroprevalence in the United States, infection remains common in some populations. Although not statistically significant, the prevalence of HSV 2 antibody among non-Hispanic blacks between the ages of 20 and 29 increased in the 1999–2004 survey compared with the previous survey conducted in 1988–1994.13 That survey did not break the population down further by gender, but in other comparisons, women had seroprevalence rates that were about twice that of men. Thus, a combined prevalence of 35% would likely represent a prevalence of about 23% in men and 46% in women. Our finding that about 34% of women at the beginning of the 20 to 29 age range were HSV 2 antibody positive is consistent with those projections. Young black women remain at very high risk of acquiring HSV 2 infection.
Black women comprise the group with the most rapid increase in HIV infection in the United States in recent years.17 The epidemiologic association of HSV 2 antibody with increased risk of HIV acquisition and the high prevalence of HSV 2 antibody in black women suggest that the 2 observations could be related. Modeling studies suggest that HSV 2 infection may be an important driver of the heterosexual HIV epidemic in sub-Saharan Africa.18 Studies that have examined the population attributable risk of HSV 2 to HIV spread1,6 show that a quarter to a third of HIV infections in black women in the United States could be related to HSV 2. Other studies have linked clinical genital herpes to HIV in black women.19 The underlying causes of disparities in the prevalence of HSV 2 and HIV in black women are complex and multifactorial.20 Our study suggests that these disparities are present from an early age.
Despite the fact that fewer than 10% of our participants knew they had genital herpes, nearly 75% of those with HSV 2 antibody shed virus from the genital tract at least once in the 13-week period that was sampled. Because we were only able to evaluate shedding once a week, unlike more typical shedding studies that evaluate subjects daily21–24 or more often,25 this must be considered a minimum estimate of the proportion of our participants who shed virus and of the frequency of shedding within individuals. Several of the participants who did not have HSV 2 shedding detected had another swab collection period assayed for various reasons and one of the participants had shedding detected in that other period (data not shown). It is possible that even more participants would have shedding detected if more specimen collection periods were assayed. In addition, vaginal swabs were the only specimens available to us for testing. Most shedding studies include other genital sites, so this may have further underestimated the number of participants who might have had detectable HSV 2 DNA. The proportion of participants shedding virus in our study was similar to that found in a previous study of subjects who were HSV 2 antibody positive but had no symptoms of genital herpes24 but somewhat higher than the placebo group in 2 other studies that evaluated suppressive antiviral therapy in HSV 2 antibody positive subjects with no history of genital herpes.26,27 The reason for these differences is not clear, but it could be because our young subjects are likely to be closer to their time of initial infection when viral shedding is more frequent.28
This study is the only one to our knowledge that prospectively collected information about genital symptoms before the participants were known to be HSV 2 antibody positive. Our finding of an association of HSV 2 shedding with genital pain in participants who did not know they had HSV 2 is unique. However, this observation is limited in at least 2 ways. First, we only collected information on 2 symptoms, pain and vaginal discharge, that were self-defined and do not represent the full spectrum of symptoms that are likely to be experienced. The second limitation is that despite demonstrating a significant association between genital pain and HSV 2 shedding, the observation has little clinical utility because of its poor positive predictive value. However, our observation does reinforce the contention that some persons with “asymptomatic” genital herpes do have subtle symptoms that they do not recognize.24,29
Our observations and those of others emphasize the need for early behavioral intervention or an HSV 2 vaccine to prevent young people, especially young black women, from becoming infected with HSV 2 and the potential downstream consequences of that event such as increased susceptibility to HIV infection. Because suppression of HSV 2 does not appear to mitigate the increased susceptibility to HIV,30,31 primary prevention of HSV 2 infection is the only viable solution. The HSV 2 vaccine that is currently in phase 3 clinical trials is only effective in women who are also HSV 1 antibody negative.32 In our earlier study of this adolescent population, 59% were HSV 1 antibody positive at age 16. Population-based studies in the United States have also shown that black Americans acquire HSV 1 infection at a relatively early age.33 We clearly need either a better HSV 2 vaccine or a strategy that intervenes at an age before most people are exposed to either HSV type. Such a strategy remains to be defined.
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