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From Medscape Education Clinical Briefs HSV2 Viral Shedding Not Removed With Antiviral Suppressive Drugs News Author: Emma Hitt, PhD CME Author: Hien T. Nghiem, MD Authors and Disclosures CME Released: 01/09/2012; Valid for credit through 01/09/2013 Clinical Context
Skin and mucosal herpes simplex virus type 2 (HSV2) shedding episodes predominantly occur in short
subclinical episodes. HSV shedding episodes are 3 times more frequent than previously realized; nearly 50%
of reactivations last less than 12 hours and are cleared by the mucosal immune system. Daily antiviral therapy
reduces genital lesions and suppresses the detection of HSV on genital mucosal surfaces (shedding). Despite
the increased use of antiviral therapy, the prevalence of, and complications from, HSV2 infection have changed
little. This discrepancy between potent suppression of clinical symptoms and failure of antiviral agents to fully
prevent HSV transmission is not well understood.
The aim of this study by Johnston and colleagues was to assess whether standard-dose or high-dose antiviral
therapy reduces the frequency of shedding during the short, subclinical periods of HSV genital reactivation.
Even high-dose antiviral suppressive therapy for HSV2 does not appear to prevent subclinical shedding of
virus, new research suggests, and this finding may explain why HSV2 continues to be transmitted even when
HSV2-positive individuals take suppressive antiviral therapy.
Christine Johnston, MD, MPH, from the Department of Medicine at the University of Washington, and from the
Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, both in Seattle, and
colleagues published their findings online January 5 in the Lancet.
According to the researchers, antisuppressive therapy for HSV2 can suppress clinical symptoms, but studies
suggest that suppressive therapy with acyclovir and valacyclovir reduces the risk for transmission only by 48%.
"The discrepancy between potent suppression of clinical symptoms and failure of antiviral agents to fully
prevent HSV transmission is not well understood," the authors note.
Dr. Johnston and colleagues also point out that short bursts of shedding, lasting less than 12 hours, are even
more frequent than can be detected by current sampling methods and account for about 70% to 85% of all
reactivations. If suppressive therapy fails to suppress these short reactivation events, then this could "account
for the lower than expected effectiveness of antiviral drugs in clinical studies of HSV-2 transmission," they
The current report describes 3 complementary crossover clinical studies that assessed whether either standard
or high doses of suppressive acyclovir or valacyclovir could affect the frequency of short, subclinical periods of
One study evaluated no medication vs acyclovir 400 mg twice daily (standard-dose acyclovir); another study
compared valacyclovir 500 mg daily (standard-dose valacyclovir) vs acyclovir 800 mg, 3 times daily (high-dose
acyclovir); and a third study evaluated standard-dose valacyclovir vs valacyclovir 1 g, 3 times daily (high-dose
Each of the test periods lasted 4 to 7 weeks, and each was separated by a 1-week wash-out phase, after which
each patient switched to the other study treatment. Genital swabs were collected 4 times daily for quantitative
Of the 113 randomized participants, 90 were eligible for analysis of within-person shedding rate, which was the
primary endpoint. A total of 23,605 swabs were collected, of which 1272 (5.4%) were HSV-positive.
HSV shedding rate was significantly higher in the no-medication group (18.1% of swabs) than in the standard-
dose acyclovir group (1.2%; incidence rate ratio [IRR] 0.05; 95% confidence interval [CI], 0.03 - 0.08). High-
dose acyclovir was associated with less shedding than was standard-dose valacyclovir (4.2% vs 4.5%; IRR,
0.79; 95% CI, 0.63 - 1.00). In addition, shedding was less frequent in the high-dose valacyclovir group than in
the standard-dose valacyclovir group (3.3% vs 5.8%; IRR, 0.54; 95% CI, 0.44 - 0.66).
The number of episodes per person per year did not differ between standard- and high-dose valacyclovir (14.9
vs 16.5; P = .34), nor did it differ between standard-dose valacyclovir and high-dose acyclovir (22.6 vs 20.2; P
= .54), but the number of episodes per person per year was lower in those taking standard-dose acyclovir than
in those taking no medication (10 vs 28.7 episodes/year; P = .001). Median episode duration was longer when
no medication was used (13 hours) compared with standard-dose acyclovir (7 hours; P = .01), as well as when
standard-dose valacyclovir was used (10 hours) compared with high-dose valacyclovir (7 hours; P = .03), but it
did not differ between standard-dose valacyclovir (8 hours) and high-dose acyclovir (8 hours; P = .23).
Similar results were found for the maximum log10 copies of HSV detected per milliliter, which was higher for no medication than for standard-dose acyclovir (3.3 vs 2.9; P = .02), and for standard-dose valacyclovir than for
high-dose valacyclovir (2.5 vs 3.0; P = .001), but no different for standard-dose valacyclovir than for high-dose
Eighty percent of episodes in all study groups were subclinical. About 30% of patients receiving high-dose
valacyclovir experienced headaches; otherwise, treatments were well tolerated.
The authors conclude that "short episodes of genital HSV shedding occur frequently with antiviral therapy, even
According to the researchers, the findings suggest that "suppressive therapies with greater potency, including
antiviral drugs or immunotherapy in the form of therapeutic vaccines, are needed to provide substantial public
health benefits, such as prevention of HSV-2 transmission and HIV-1 acquisition and transmission."
In a related editorial, Philippe Van de Perre, MD, and Nicolas Nagot, MD, both from the Université Montpellier
in France, point out that these findings "should encourage patients to use condoms and adopt safe sex
practices, especially since increase of the treatment dose would not further reduce the risk of transmission to
"The development of new antiherpetic drugs such as helicase–primase inhibitors is important," they add.
"Alternative control tools, such as immunotherapeutic strategies (therapeutic vaccines), are in preclinical
development, but they are hampered by the absence of an adequate animal model and the lack of commitment
from pharmaceutical companies and the public sector."
The study was supported by the National Institutes of Health. In one of the studies, GlaxoSmithKline provided
valacyclovir at no cost. Several of the study authors have relevant financial associations with companies
developing anti-HSV approaches. Dr. Johnston is a research investigator for AiCuris, GmbH. The editorialists
have disclosed no relevant financial relationships.
Lancet. Published online January 5, 2012.
In this study, HSV2-seropositive, HIV-seronegative people were enrolled at the University of
Washington Virology Research Clinic between November 2006 and July 2010.
In trial 1, patients with both symptomatic and asymptomatic genital herpes were recruited. In trials 2
and 3, participants needed to have had at least 4 clinical HSV2 recurrences in the previous year or
laboratory-documented primary genital HSV2 in the previous 6 months.
Participants with adverse reactions to acyclovir, pregnant women, and those unable to comply with
3 separate, but complementary, open-label crossover studies compared no medication vs acyclovir
400 mg twice daily (standard-dose acyclovir), valacyclovir 500 mg daily (standard-dose valacyclovir)
vs acyclovir 800 mg three times daily (high-dose acyclovir), and standard-dose valacyclovir vs
valacyclovir 1 g three times daily (high-dose valacyclovir).
The allocation sequence was generated by a random number generator.
Study drugs were supplied in identical, numbered, sealed boxes.
Study periods lasted 4 to 7 weeks, separated by a 1-week washout.
Participants collected genital swabs 4 times daily for quantitative HSV DNA polymerase chain reaction.
Clinical data were masked from laboratory personnel.
The primary endpoint was within-person comparison of shedding rate in each study group.
Of 113 participants randomly assigned, 90 were eligible for analysis of the primary endpoint.
The demographics of the study population were similar in each of the trials.
Participants collected 23,605 swabs; 1272 (5.4%) were HSV positive.
The frequency of HSV shedding was significantly higher in the no-medication group (n = 384, 18.1% of
swabs) vs the standard-dose acyclovir group (n = 25, 1.2% of swabs; IRR, 0.05; 95% CI, 0.03 - 0.08).
High-dose acyclovir was associated with less shedding than standard-dose valacyclovir (198 [4.2%] vs
209 [4.5%]; IRR, 0.79; 95% CI, 0.63 - 1.00).
Shedding was less frequent in the high-dose valacyclovir group vs the standard-dose valacyclovir
group (164 [3.3%] vs 292 [5.8%]; IRR, 0.54; 95% CI, 0.44 - 0.66).
In total, 344 genital HSV shedding episodes occurred, and 80% of shedding episodes were subclinical
The number of episodes per person-year did not differ significantly for standard-dose valacyclovir
(22.6) vs high-dose acyclovir (20.2; P = .54), and standard-dose valacyclovir (14.9) vs high-dose
valacyclovir (16.5; P = .34). However, the number of episodes per person-year did differ for no
medication (28.7) and standard-dose acyclovir (10.0; P = .001).
Median duration of episodes was longer for no medication vs standard-dose acyclovir (13 hours vs 7
hours; P = .01) and for standard-dose valacyclovir vs high-dose valacyclovir (10 hours vs 7 hours; P =
.03). However, it did not differ significantly between standard-dose valacyclovir and high-dose
acyclovir (8 hours vs 8 hours; P = .23).
Likewise, the maximal log10 copies of HSV detected per milliliter were higher for no medication vs standard-dose acyclovir (3.3 vs 2.9; P = .02) and for standard-dose valacyclovir vs high-dose
valacyclovir (2.5 vs 3.0; P = .001), but no significant difference was recorded for standard-dose
valacyclovir vs high-dose acyclovir (2.7 vs 2.8; P = .66).
Except for a higher frequency of headaches with high-dose valacyclovir (n = 13; 30%) vs other
regimens, all regimens were well tolerated.
Shedding in HSV2 predominantly occurs in short, subclinical episodes.
Despite high-dose antiherpetic therapy, short bursts of subclinical genital reactivation of HSV are
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