Asymptomatic Shedding of Herpes Simplex Virus 1 and 2:
Implications for Prevention of Transmission
Gregory J. Mertz
Department of Internal Medicine, University of New Mexico, Albuquerque
(See the article by Mark et al., on pages XXX–XXX.)
sion 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 aver-
age duration of shedding is much longer
when lesions are present [1, 2], and the
risk of transmission following a single
higher than a single contact with asymp-
tomatic shedding. More than 2 decades
transmission of HSV was suggested by
evaluation of recent sex partners impli-
cated in transmission of genital herpes
and by evaluation of mothers who trans-
mitted HSV to neonates yet lacked a his-
tory of genital herpes [3–6].
partners of persons with first-episode
genital herpes were interviewed and eval-
mine the source of sexual transmission
and whether the source partner had
herpes at the time of transmission .
Among 66 recent sex partners identified
as the source partner, only 29 (44%) gave
sions were present. Transmission of gen-
ital 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 iso-
lated 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 bi-
ased. It was also difficult to imagine that
asymptomatic shedding could be respon-
sible for more than half of the sexual
able through the 1980s, which were based
on virus culture, suggested that asymp-
tomatic genital shedding of HSV-2 oc-
curred as infrequently as 1% of days in
the risk of transmission during periods of
tions of proven efficacy could be recom-
available regarding the effectiveness of
routine condom use between symptom-
atic episodes, and one preliminary report
even suggested that antiviral therapy
tomatic shedding .
The concern regarding recall bias by
a prospective study in 144 heterosexual
couples with 1 symptomatic partner with
genital herpes and 1 asymptomatic part-
without detectable HSV-2 antibody at
study entry . In this study, both part-
ners kept diaries recording each sexual
of symptoms or lesions in the symptom-
(9.7%) of the couples, including 13 in
period when transmission occurred. Al-
though 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 re-
sulted from sexual contact when the
source partner reported no symptoms or
The frequency of asymptomatic shed-
studies based on detection of viral shed-
ding by polymerase chain reaction (PCR)
amplification of viral DNA, which is far
more sensitive than virus culture . In
these studies, asymptomatic shedding
from anogenital sites was documented
Received 6 June 2008; accepted 6 June 2008; electroni-
cally published XX August 2008.
Potential conflicts of interest: The University of New Mex-
ico Department of Internal Medicine has received grant
funding from Astellas Pharma, which is developing an anti-
viral drug for herpes simplex virus infections, and from the
National Institutes of Health, which is evaluating the efficacy
of an HSV vaccine developed by GlaxoSmithKline. G.M.
receives no direct salary support for these activities.
Reprints or correspondence: Dr. Gregory Mertz, Internal
Medicine, MSC10 5550, 1 University of New Mexico, Albu-
querque, NM 87131–0001 (firstname.lastname@example.org).
The Journal of Infectious Diseases
© 2008 by the Infectious Diseases Society of America. All
E D I T O R I A L C O M M E N T A R Y
● JID 2008:198 (15 October)
by guest on February 2, 2016
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
significantly reduced the frequency of
asymptomatic shedding [12, 16, 19], and
daily suppressive therapy with valacyclo-
vir decreased both the frequency of
asymptomatic shedding and the risk of
transmission of genital HSV infection
tween episodes was also shown to reduce
the risk of transmission of genital herpes
In the PCR-based shedding studies de-
scribed above, samples were collected
once daily. However, recent mathemati-
cal modeling studies suggest that shed-
ding episodes might be caused by multi-
ple short overlapping episodes rather
than single reactivations [21, 22], and a
sistence of HSV-specific T cells contigu-
ous to sensory nerve endings may rapidly
clear local reactivations. In this issue of
sults of a prospective study of oral shed-
ding 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 du-
ration was 13 h. Oral shedding was de-
tected on 12% of 691 days during which
all 4 samples were collected, and the me-
dian duration of shedding was 24 h. Re-
markably, ?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
sample positive by PCR.
One important conclusion that can be
drawn from the results of the study by
Mark et al. , the previous PCR-based
shedding studies [12–16], and the once
is that there is now enough data to con-
sider PCR-based measurement of asymp-
tomatic shedding rates as a surrogate
antiviral therapy with one of the HSV
DNA polymerase inhibitors (i.e., acyclo-
vir, valacyclovir, or famciclovir) signifi-
completely suppress, shedding [12, 16,
17, 19], and once daily valacyclovir ther-
apy reduces the risk of transmission by
?50% among persons with a history of
up to 9 episodes per year . 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 modula-
tor such as resiquimod applied to lesions
, an antiviral medication with a dif-
ferent target such as a helicase-primase
tion 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 large-
plete suppression can be demonstrated.
Although the study by Mark et al. 
is limited to immunocompetent adults,
their results may also contribute to our
understanding of the interaction of
HSV-2 and HIV in acquisition and trans-
mission 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 .
Although acyclovir 400 mg by mouth
twice daily did not decrease the incidence
of HIV infection among women in Tan-
zania, adherence based on pill counts was
suboptimal, and there was no significant
decrease in asymptomatic genital shed-
In HIV-infected persons, HSV-2 coin-
fection leads to activation of latent HIV
and to increased quantities of HIV RNA
in genital secretions [31–34] and plasma
, and asymptomatic shedding of
HSV-2 is associated with higher fre-
quency and amount of HIV-1 RNA in
genital secretions . In some studies
performed before the availability of
highly active antiretroviral therapy, the
addition of acyclovir to mono- or dual-
nucleoside inhibitor antiretroviral ther-
apy prolonged survival [37, 38], and
treatment with high-dose oral acyclovir
led to decreases in plasma HIV-1 RNA
levels . In 2 recent studies involving
HSV-2 who were not receiving antiretro-
viral therapy, treatment with valacyclovir
500 mg 2 times daily resulted in decreases
in mean plasma HIV-1 RNA loads of
0.33–0.53 log10copies/mL [36, 40]. On-
going trials should determine whether
these decreases in HIV load lead to de-
Finally, what should we tell our pa-
tients regarding asymptomatic shedding
genital herpes should be counseled that
simply avoiding sexual contact when le-
sions are present is not adequate for pre-
vention of transmission and that asymp-
tomatic shedding is frequent and is the
most common mechanism of transmis-
sion to sex partners. Patients can also be
abstinence can provide complete protec-
tion, the risk of transmission can be sig-
nificantly reduced by both suppressive
antiviral therapy and regular use of con-
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