Genital Herpes: Silent Spread
November 26th, 2008 | by admin |Genital herpes is one of the most prevalent sexually transmitted infections in the world today; approximately 45 million adults in the United States are seropositive for herpes simplex virus type 2 (HSV-2). Although the infection itself is generally not life-threatening, it has a significant morbidity and impact on patients’ lives, and has profound public health implications with respect to the transmission and acquisition of other sexually transmitted infections, including HIV infection.
The ability of HSV-2 to establish latency in sensory nerve ganglia and to undergo periodic reactivation and frequent asymptomatic shedding across mucosal surfaces creates a lifelong potential for transmission to sexual partners and for the possibility of neonatal infection in pregnant women. Further, HSV-2 infection has been demonstrated to significantly increase the transmission and risk of acquisition of HIV. At present, there is no cure for genital herpes infection, but treatment strategies are available to alleviate the acute symptoms of herpes outbreaks, suppress recurrences, reduce asymptomatic shedding, and lower the risk of transmission.
Oral antiviral therapy, until recently, had been prescribed for patients with genital herpes either to alleviate the acute symptoms and signs of an outbreak (initial or episodic treatment) or to prevent HSV reactivation and the subsequent development of recurrent outbreaks (suppressive therapy). The use of chronic, daily antiviral therapy to reduce transmission of genital herpes is a new indication and signifies the most significant development in the management of genital herpes since the introduction of acyclovir.
A Disease of Frequent Viral Shedding
Two factors have contributed greatly to the continuing issue of new transmission events. First, although genital herpes is common, infection is rarely recognized. Second, reactivation of genital infection is the norm with nearly 100% of individuals experiencing reactivation of infection either clinically or asymptomatically. Thus, the notion of separating genital HSV-2 infection into 2 separate categories of “infection” and “disease” is at best overly simplistic and probably antiquated. The presence of HSV-2 on the genital mucosal surface, whether associated with clinically recognized outbreaks, subclinical outbreaks, or asymptomatic shedding, can and does lead to the transmission of HSV-2.
We now understand that genital herpes infection due to HSV-2 is one of frequent viral shedding. During the first 6 months of infection, shedding can occur during 20% to 40% of days; with longer-term infection, shedding may occur during 5% to 20% of days. It is the shedding of virus – and particularly asymptomatic viral shedding – that is responsible for the transmission of genital herpes. Asymptomatic viral shedding is the presence of virus in the absence of clinical signs or symptoms. Up to 70% of new infections can be attributed to asymptomatic shedding. Asymptomatic shedding occurs in virtually all HSV-2 infected patients, and shedding rates cannot be predicted on the basis of age, sex, or reported history of outbreaks. Shedding of virus can occur from multiple genital sites, and 50% of asymptomatic shedding events occur more than 7 days before or after a clinical outbreak. And although viral shedding tends to diminish over the course of infection, the rate of decay is measured in years and the potential of transmission persists.
HSV-2 Shedding, Transmission, and Prevention
Because we cannot answer the when and where of viral shedding, but can affirm the who (nearly all infected individuals), the great challenge of dealing with genital herpes has been how to prevent transmission. Until recently, counseling guidelines to reduce transmission risk called for patients to disclose their infection status to sexual partners, recognize and abstain from sex during outbreaks, and use condoms during all sexual encounters. Before 2002, despite accumulating evidence that unrecognized viral shedding was the driving force behind the spread of genital herpes, antiviral management practices focused solely on the treatment of disease in affected individuals. Episodic therapy, which relies by definition on the recognition of signs and symptoms associated with genital herpes, could not be expected to have a substantial impact on asymptomatic shedding. Suppressive antiviral therapy likewise remained strictly in the therapeutic realm, being reserved for individuals with a recognized “significant” number and/or severity of outbreaks. (Other benefits were considered by many as “softer,” and served to reduce the psychologic burden of a lifelong, chronic sexually transmitted infection ). Even with the demonstration in the early 1990s that the use of daily antiviral therapy could reduce viral shedding by 85% to 95%, the question remained as to whether this was sufficient to reduce transmission risk.
That question was answered by the landmark study of Lawrence Corey and colleagues, which demonstrated that daily suppressive therapy with valacyclovir not only reduced the frequency of viral shedding in HSV-2 infected individuals, but significantly reduced the transmission of genital herpes infection among monogamous, heterosexual, HSV-2 serodiscordant couples. The acquisition of HSV-2 by susceptible partners was reduced by 48% (P = .054), and the occurrence of clinical disease was reduced by 75% (P = .01). The time to overall acquisition of infection was decreased by 55% with the use of suppressive therapy (P = .012). Significantly, these clinical findings were eloquently shown to be correlates of the virologic effects of chronic, daily valacyclovir therapy: Viral shedding was detected on 2.9% of days among HSV-2 infected partners who received valacyclovir as compared with 10.8% of days among those who received placebo (P < .001).
This study established that reductions in viral shedding effected by suppressive antiviral therapy are associated with reductions in the transmission of HSV-2 to susceptible partners. On the individual level, the importance of these findings is immense and should be considered in the full context of previously demonstrated benefits of suppressive antiviral therapy, which include improvements in the psychologic, sexual, and physical well-being of both infected and susceptible partners. On the population level, epidemiologic models have suggested that suppressive antiviral therapy would not have a significant impact on the overall prevalence of genital herpes, but could reduce incidence. Key questions in this regard are whether suppressive therapy could indeed result in an incidence shift and what impact such a shift might have on secondary outcomes of genital herpes infection, such as the acquisition of HIV and neonatal herpes. Studies of the effects of episodic and suppressive therapy on HIV incidence are currently being conducted. The importance and urgency of these studies cannot be overstated.
There are several limitations to the study of Corey and colleagues that are worth mentioning. First, the study period lasted 8 months; hence, there are no data that show a benefit of transmission reduction beyond that period. Kaplan-Meier analyses of both HSV-2 acquisition and shedding remained divergent throughout the study period, but with continued benefit of valacyclovir over placebo for the course of the study. In this regard, previous studies of suppressive therapy in immunocompetent patients have shown continued benefit of therapy for years. Long-term studies of the effects of antiviral therapy on genital herpes transmission will almost certainly never be done. However, if asymptomatic shedding rates are viewed as a surrogate marker for transmission risk, the benefit of suppressive therapy should well exceed the duration of the study period of the Corey trial.
Second, the study population included only mutually monogamous, heterosexual, HSV-2 discordant couples. There is certainly no biological reason, however, to believe nonmonogamous individuals would not derive a similar benefit in transmission reduction with suppressive therapy. The benefits of suppressive therapy appear to be no different for men and women; it remains to be determined whether similar reductions in transmission will be seen among men who have sex with men.
Third, the study did not address the factors or conditions associated with increased viral shedding, such as coinfection with HIV or incident HSV infection. Such conditions warrant further studies, which may be able to be accomplished by looking at the impact of therapy on subclinical shedding.
Conclusions
Although it has long been evident that asymptomatic viral shedding of HSV-2 is responsible for the vast majority of new genital herpes infections, and that suppressive antiviral therapy can significantly reduce the frequency of viral shedding, it has only recently been established that reductions in viral shedding effected by suppressive antiviral therapy correlate with reductions in the transmission of genital herpes. Given the safety of all currently available antivirals for genital herpes, as well as the lack of resistance to acyclovir seen in chronic use in immunocompetent hosts, chronic suppressive therapy is now an essential component of strategies for reducing the risk of HSV-2 transmission. Dissemination of the findings of the transmission study of Corey and colleagues coupled with increased awareness of the role of asymptomatic viral shedding in the spread of genital herpes will hopefully go a long way toward increasing the consideration of suppressive therapy by both clinicians and patients.
