Asymptomatic Shedding of Herpes Simplex Virus 1 and 2: Implications for Prevention of Transmission

It is counterintuitive that sexual transmission of herpes simplex virus (HSV) more commonly results from contact during a short episode of asymptomatic shedding than from contact with lesions. After all, virus titers are much higher and the average duration of shedding is much longer when lesions are present [1, 2], and the risk of transmission following a single contact with lesions is undoubtedly much higher than a single contact with asymptomatic shedding. More than 2 decades ago, the role of asymptomatic shedding in transmission of HSV was suggested by evaluation of recent sex partners implicated in transmission of genital herpes and by evaluation of mothers who transmitted HSV to neonates yet lacked a history of genital herpes [3–6]. In a study published in 1985, recent sex partners of persons with first-episode genital herpes were interviewed and evaluated with clinical examination, viral culture and herpes antibody testing to determine the source of sexual transmission and whether the source partner had symptoms and was known to have genital herpes at the time of transmission [3]. Among 66 recent sex partners identified as the source partner, only 29 (44%) gave a history of recent sexual contact when lesions were present. Transmission of genital herpes in most study subjects (37 [56%]) appeared to have resulted from sexual contact in the absence of lesions or symptoms, and 23 of 66 source contacts, including 2 from whom HSV-2 was isolated from the cervix, had no history of oral or genital herpes. Although this study raised concern about the potential risk of transmission during asymptomatic shedding, there were justifiable concerns that histories provided by source partners might be biased. It was also difficult to imagine that asymptomatic shedding could be responsible for more than half of the sexual transmission of HSV when the data available through the 1980s, which were based on virus culture, suggested that asymptomatic genital shedding of HSV-2 occurred as infrequently as 1% of days in women and was difficult to detect at all in men [7–10]. There was no way to estimate the risk of transmission during periods of asymptomatic shedding, and no interventions of proven efficacy could be recommended short of abstinence. No data were available regarding the effectiveness of routine condom use between symptomatic episodes, and one preliminary report even suggested that antiviral therapy might not reduce the frequency of asymptomatic shedding [4]. The concern regarding recall bias by the source partners was largely resolved in a prospective study in 144 heterosexual couples with 1 symptomatic partner with genital herpes and 1 asymptomatic partner without a history of genital herpes and without detectable HSV-2 antibody at study entry [11]. In this study, both partners kept diaries recording each sexual contact, as well as the presence or absence of symptoms or lesions in the symptomatic partner. Transmission occurred in 14 (9.7%) of the couples, including 13 in which diaries were maintained during the period when transmission occurred. Although 4 couples (31%) reported sexual contact during the prodrome (1 case) or within hours before lesions were first noted by the symptomatic partner (3 cases), in 9 cases (69%) transmission resulted from sexual contact when the source partner reported no symptoms or lesions. The frequency of asymptomatic shedding was clarified in a series of prospective studies based on detection of viral shedding by polymerase chain reaction (PCR) amplification of viral DNA, which is far more sensitive than virus culture [1]. In these studies, asymptomatic shedding from anogenital sites was documented in 80%–90% of seropositive men and women, was present on ~20% of days with daily sampling, and was present at even higher frequency during the first 3 months after acquisition of first-episode genital herpes [12–18]. Treatment with oral acyclovir, valacyclovir, or famciclovir significantly reduced the frequency of asymptomatic shedding [12, 16, 19], and daily suppressive therapy with valacyclovir decreased both the frequency of asymptomatic shedding and the risk of transmission of genital HSV infection [17]. In addition, routine condom use between episodes was also shown to reduce the risk of transmission of genital herpes [20]. In the PCR-based shedding studies described above, samples were collected once daily. However, recent mathematical modeling studies suggest that shedding episodes might be caused by multiple short overlapping episodes rather than single reactivations [21, 22], and a report by Zhu et al. [23] suggests that persistence of HSV-specific T cells contiguous to sensory nerve endings may rapidly clear local reactivations. In this issue of the Journal, Mark et al. [24] report the results of a prospective study of oral shedding in 18 HSV-1-seropositive healthy adults and anogenital shedding in 25 HSV-2-seropositive healthy adults who collected samples 4 times daily for 60 days. Anogenital shedding was detected on 20% of 962 days, and the median duration was 13 h. Oral shedding was detected on 12% of 691 days during which all 4 samples were collected, and the median duration of shedding was 24 h. Remarkably, >20% of anogenital and oral reactivations lasted ⩽6 h, and 49% of anogenital reactivations and 39% of oral reactivations lasted ⩽12 h. Overall, 84% of subjects collecting genital swabs and 83% of those collecting oral swabs had ⩾1 sample positive by PCR. One important conclusion that can be drawn from the results of the study by Mark et al. [24], the previous PCR-based shedding studies [12–16], and the once daily valacyclovir transmission study [17] is that there is now enough data to consider PCR-based measurement of asymptomatic shedding rates as a surrogate marker for transmission risk. Suppressive antiviral therapy with one of the HSV DNA polymerase inhibitors (i.e., acyclovir, valacyclovir, or famciclovir) significantly reduces the frequency, but does not completely suppress, shedding [12, 16, 17, 19], and once daily valacyclovir therapy reduces the risk of transmission by ~50% among persons with a history of up to 9 episodes per year [17]. As such, other strategies should be explored in an attempt to further reduce the frequency of asymptomatic shedding and the risk of transmission. Whether the strategy uses a therapeutic vaccine, an immune modulator such as resiquimod applied to lesions [25], an antiviral medication with a different target such as a helicase-primase inhibitor [26], or ⩾1 of these in combination with one of the currently approved HSV DNA polymerase inhibitors, it would seem prudent to first evaluate the regimen in a small, PCR-based shedding study and to only consider another largescale transmission study when more complete suppression can be demonstrated. Although the study by Mark et al. [24] is limited to immunocompetent adults, their results may also contribute to our understanding of the interaction of HSV-2 and HIV in acquisition and transmission of HIV-1 infection. The risk of acquisition of HIV infection is increased by HSV-2 infection [27, 28], particularly when acquisition of HSV-2 is recent [29]. Although acyclovir 400 mg by mouth twice daily did not decrease the incidence of HIV infection among women in Tanzania, adherence based on pill counts was suboptimal, and there was no significant decrease in asymptomatic genital shedding of HSV-2 among the acyclovir recipients [30]. In HIV-infected persons, HSV-2 coinfection leads to activation of latent HIV and to increased quantities of HIV RNA in genital secretions [31–34] and plasma [35], and asymptomatic shedding of HSV-2 is associated with higher frequency and amount of HIV-1 RNA in genital secretions [36]. In some studies performed before the availability of highly active antiretroviral therapy, the addition of acyclovir to mono- or dualnucleoside inhibitor antiretroviral therapy prolonged survival [37, 38], and treatment with high-dose oral acyclovir led to decreases in plasma HIV-1 RNA levels [39]. In 2 recent studies involving men and women coinfected with HIV and HSV-2 who were not receiving antiretroviral therapy, treatment with valacyclovir 500 mg 2 times daily resulted in decreases in mean plasma HIV-1 RNA loads of 0.33–0.53 log10 copies/mL [36, 40]. Ongoing trials should determine whether these decreases in HIV load lead to decreased transmission or result in a delay in disease progression. Finally, what should we tell our patients regarding asymptomatic shedding and the risk of transmission? Patents with genital herpes should be counseled that simply avoiding sexual contact when lesions are present is not adequate for prevention of transmission and that asymptomatic shedding is frequent and is the most common mechanism of transmission to sex partners. Patients can also be counseled that, although nothing short of abstinence can provide complete protection, the risk of transmission can be significantly reduced by both suppressive antiviral therapy and regular use of condoms.