Seven years ago, an editorial published in this journal called for studies to clarify the role of antiviral treatment in preventing the transmission of genital herpes.1 In the intervening years, seroprevalence studies in the United States have shown that the rate of infection with herpes simplex virus type 2 (HSV-2) has risen to 22%,2 whereas in Europe, rates between 4% and 44% have been reported.3 Support for an association between HSV-2 and HIV acquisition and transmission has increased, and anxiety about infecting their sexual partner is still among the top three concerns of people with genital herpes.4-6 We know that antiviral treatment reduces symptomatic and asymptomatic shedding of HSV from genital mucosa,7-9 but until now we have not known whether this would translate into a real, clinically important reduction in the transmission of genital herpes to an uninfected partner.
A recently published study was undertaken in 1484 heterosexual, immunocompetent couples to determine if daily valaciclovir could reduce the sexual transmission of genital herpes.10 One partner of each couple had clinically diagnosed genital HSV-2 infection, and the other was HSV-2 seronegative. The infected partners were randomised to valaciclovir 500 mg once daily or placebo for eight months. Both partners were followed for clinical signs and symptoms of genital HSV infection, counselled on safer sex practices, and offered condoms at each visit. Symptomatic genital herpes was observed in the partners of 2.2% of individuals treated with placebo and 0.5% of those treated with valaciclovir (75% reduction in relative risk). Evidence (polymerase chain reaction, serology, or cell culture) of HSV-2 acquisition was present in 3.6% of couples in the placebo group and 1.9% of those in the valaciclovir group (hazard ratio 0.52, 95% confidence interval 0.27 to 0.99, P = 0.04). Genital herpes was less often transmitted in couples using condoms, but the benefit of valaciclovir was additional to the protective effect of condoms. None of the 141 individuals who took valaciclovir and used condoms for more than 90% of sexual encounters transmitted symptomatic genital herpes to their partner.
The rate of transmission in these monogamous HSV-2 discordant couples was very low, at under 5% over an eight month period, and we can speculate about reasons for this. Firstly, the study recruited women as the infected partners in 67% of couples, so most of the uninfected, seronegative partners were men. Men may be up to four times less susceptible to acquiring genital herpes than women (P = 0.006), so a low transmission rate was to be expected in this study.11 Secondly, all couples enrolled in the study were motivated to try to prevent the transmission of infection and were explicitly advised to abstain from sexual intercourse during recurrences and to use condoms for every sexual encounter. Such measures are central to the current behavioural approach to reducing the risk of transmission of genital herpes. In assessing the cost effectiveness of this intervention in data from a population with such a low rate of sexual HSV transmission, it may therefore be valuable to model these effects in populations at greater risk of transmission. These include people who are less motivated to follow behavioural advice or in scenarios where people change sexual partners often. Also covariables should be examined, such as concurrent HIV transmission, to inform decision making on the public health effectiveness of this intervention in targeted groups.
In clinical practice, which individuals would benefit most from suppressive antiviral treatment to reduce the transmission of genital herpes to a partner? HSV-2 infection often goes undiagnosed and may be asymptomatic. Individuals with asymptomatic HSV-2 infection, even if diagnosed, will not themselves benefit from the suppressive effect of continuous antiviral therapy. However, if the risk of transmission of infection is causing anxiety even patients who do not find their own symptoms bothersome may benefit from a period of antiviral suppression, which can be linked to behavioural sexual health advice. Patients who are already taking suppressive drugs may find it reassuring to know that the medication they are taking to control their own symptoms is also helping to protect their sexual partner.
In the United States the results of this study have led the Food and Drug Administration to approve a new indication for valaciclovir—the prevention of sexual transmission of HSV infection. However, it must be emphasised that these new data were obtained in immunocompetent, heterosexual couples who were motivated to enrol in a trial. How the benefits will be altered by adherence to treatment or whether antiviral suppression affords protection of HSV transmission in other scenarios—such as during pregnancy, across same sex relationships, or among individuals with HIV infection—requires measured clinical judgment until further studies are available. Furthermore, the vexed question remains of whether the notable reduction in transmission provided by valaciclovir would be achieved by other antiviral drugs, such as aciclovir or famciclovir, and if so, at what dose? Without comparative data, individual prescribing decisions in specific healthcare settings will need to be made on the basis of factors including availability, potential adherence, and cost.
That no evidence of viral resistance was detected in those individuals who became infected in this study is reassuring. That some susceptible individuals did become infected reinforces the message that valaciclovir reduced the frequency of HSV reactivation, subclinical shedding, and transmission of genital herpes, but it did not eliminate it. Antiviral treatment is thus not a substitute for other methods to control the spread of sexually transmitted infections but an additional tool. Patients should also be advised to continue using condoms, practise safer sex, and inform their partner about transmissible infections they have. The risk of transmitting genital herpes will not be removed, but patients can be assured that they are doing everything they can to reduce the risk of infecting a loved one.