[Not really new news, but it just popped into my email box, and I
thought I'd break all the rules and pass it on.  There's some good
info in there, kind of a what-we-know-now recap, which is handy
since we're learning all the time.  I'll be gone a few days so feel
free to talk about me.  ;-)  Mike]

http://www.medscape.com/viewarticle/478550?src=mp

June 2, 2004
From Medscape Infectious Diseases

Expert Column
Asymptomatic Shedding in the Transmission, Prevention, and Treatment
of Genital Herpes
Posted 05/27/2004

Peter Leone, MD, IDSA, CSTE, NCSD

Introduction

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).[1] Although the infection itself is generally not
life-threatening, it has a significant morbidity and impact on
patients' lives,[2] and has profound public health implications with
respect to the transmission and acquisition of other sexually
transmitted infections, including HIV infection.[3,4]

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.[3-5] 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.[1,6] Second, reactivation of genital
infection is the norm with nearly 100% of individuals experiencing
reactivation of infection either clinically or asymptomatically.[7]
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.[7] 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.[8-10] 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.[7,11] 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.[7] 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.[12] 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.[13,14]

That question was answered by the landmark study of Lawrence Corey
and colleagues,[15] 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[15] 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.[16] 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.[17,18] 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.[4]

There are several limitations to the study of Corey and
colleagues[15] 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.[19,20] 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[15] 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.

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