Interrupting transmission of genital herpes

HSV-2 is endemic in many parts of the world, yet most people are unaware that they have this infection. The minority of individuals in whom the infection has been diagnosed are largely untreated and subclinical reactivation the norm. Sexual transmission routinely occurs from such asymptomatic reactivations and so most transmitters remain unaware of their contagious status [1]. It is thus perhaps not surprising that the seroprevalence of HSV-2 antibodies has increased in two USA national serosurveys (conducted during 1976–1980 and 1988–1994) so that overall 22% of US citizens in the later study were HSV-2 seropositive [2]. This increase in seroprevalence was found in both females and males, although females continue to have a higher absolute seroprevalence than males [2]. HSV-2 seroprevalence increases in proportion to the number of lifetime sexual partners but this virus frequently infects individuals with modest sexual experience [2]. Since HSV-2 seroprevalence has increased during the era of widespread advice about safer-sex guidelines to prevent acquisition of HIV, we can conclude that the public is refractory to such generic advice and so need specific interventions to provide protection against HSV-2. The view that HSV-2 is a latent virus with only occasional periods of reactivation has been transformed by a series of studies from investigators in Seattle. In women who self-collected daily swabs from the vulva, cervix and rectum for 105 days, HSV-2 was cultured on 6% of days, corresponding on one-third of occasions with subclinical infection [3]. Comparable figures were obtained in heterosexual men [4] and HIVnegative homosexual men [5]. Likewise, subclinical shedding was found at similar rates in HSV-2 seropositive individuals who did, or did not, have a history of clinical genital herpes [6]. Men who were HIV positive had higher daily rates (9%) of positive anogenital cultures [7]. Using PCR, which is approximately four times more sensitive for detecting HSV on mucocutaneous surfaces than is conventional cell culture, investigators have shown that asymptomatic shedding from the genital tract of all populations is even more common [8] clearly illustrating how HSV-2 may be spread readily from person to person. There have been several controlled attempts to interrupt transmission of HSV-2 using groups of monogamous heterosexual couples where one partner is seropositive for HSV-2 but the other is uninfected. At trial entry and at each clinic visit, such couples were given counselling about safer sex guidelines including the use of condoms and various interventions were evaluated in randomised placebo-controlled trials. Administration of HSV-2 vaccine (either glycoprotein D plus glycoprotein B plus MF59 adjuvant or glycoprotein D plus alum plus monophosphoryl lipid A adjuvant) to seronegative men was no better at preventing acquisition of genital herpes disease than was placebo [9,10]. However, the same vaccine preparations had a better response in women; an effect that was limited to those women who were seronegative for HSV-1 as well as HSV-2 at the start of the study [10]. Although the studies were not masked for condom use (indeed, it is difficult to imagine how one could design a placebo condom) the data from one study have been analysed to determine if condom use correlated with reduced transmission. Accordingly, a lower rate of acquiring HSV-2 was reported, with a hazard ratio of 0.08 for women reporting condom use for at least 25% of sexual acts (the number of males acquiring HSV infection was too small to allow a conclusion to be drawn) [11]. However, while the results provide evidence in favour of a protective effect of condoms, their use was too infrequent to allow them to interrupt transmission of HSV-2 at the population level. Could antiviral drugs be used to interrupt transmission? A series of crossover controlled clinical trials of aciclovir, valaciclovir and famciclovir has shown that asymptomatic shedding of HSV DNA from the genital tract is reduced dramatically by each of these drugs [12,13]. However, it cannot be assumed that this reduced asymptomatic E D I T O R I A L