Canadian Guidelines on Sexually Transmitted Infections
[Table of Contents]
Review of the recent evidence related to the use of HSV suppressive therapy among HIV co-infected patients as published in the Canada Communicable Disease Report
Section 5 - Management and Treatment of Specific Infections
Genital Herpes simplex virus (HSV) Infections
- Herpes simplex virus (HSV) types 1 and 2.
- The annual incidence in Canada of genital herpes
due to HSV-1 and -2 infection is not known (for a review of HSV-1/HSV-2
prevalence and incidence studies worldwide, see Smith and Robinson 2002).
In the United States, it is estimated that about 1,640,000 HSV-2
seroconversions occur yearly (730,000 men and 910,000 women, or 8.4 per 1,000
- Based on the change in prevalence of the serum
antibody to HSV-2, HSV-2 increased 30% between 1976 and 1994, from 16.4-21.9%
in Americans aged 12 years and older.
- In British Columbia in 1999, the seroprevalence
of HSV-2 antibody in leftover serum submitted for antenatal testing revealed a
prevalence of 17.3%, ranging from 7.1% in women 15-19 years old to 28.2% in
those 40-44 years.
- In attendees at an Alberta sexually transmitted
infection (STI) clinic in 1994 and 1995, the seroprevalence of HSV-1 and -2 in
leftover sera was 56% and 19%, respectively.
- The incidence and prevalence of HSV-1 genital
infection is increasing globally, with marked variation between countries.
- In Norway, a recent study found that 90% of
genital initial infections were due to HSV-1.
- In Nova Scotia, 58.1% of 1,790 HSV isolates from
genital lesion cultures in women were HSV-1; in men, 36.7% of 468 isolates were
- Females are at higher risk of acquiring genital
herpes from a male partner than males are from a female partner. Studies have
found that among discordant heterosexual couples with a source partner who had
symptomatic recurrent genital HSV-2 infection, the annual transmission rates
were 11-17% in couples with male source partners and 3- 4% in couples with
female source partners.,
- In one study, transmission in 70% of patients
appeared to result from sexual contact during periods of asymptomatic virus
- Pre-existing seropositivity to HSV-1 reduced the
likelihood of acquiring symptomatic genital HSV-2 disease in women by 55-74%,, although others have not observed such a protective effect.,
- The incubation period averages 6 days.
- Of new HSV-2 infections diagnosed by seroconversion,
approximately 60% are asymptomatic and 40% symptomatic. Of the symptomatic
cohort, about 80% present with typical genital symptoms and signs, while 20%
have atypical presentations, including nonlesional HSV-2 infections such as
genital pain or urethritis, aseptic meningitis and cervicitis, which are
well-recognized complications of first episodes of genital HSV infection.
- No intervention, including early initiation of
antiviral therapy, prevents the development of latent sacral sensory ganglion
- Recurrences tend to occur in tissues innervated
by sacral sensory nerves.
- Recurrences may be preceded by warning signs
(prodromal symptoms) a few minutes to several days before lesions appear, such
as focal burning, itching (most common), tingling or vague discomfort. Recurrences may be associated with the menstrual cycle, emotional stress,
illness (especially with fever), sexual intercourse, surgery and certain
medication — so-called “trigger factors.”
- Initial mean recurrence rates are greater in
persons with genital HSV-2 infection than in those with HSV-1: 4% and 1% per
year, respectively, with marked individual variation.
- The average recurrence rate decreases over time
by around 0.8 outbreaks per year, every year (no matter how high the initial
outbreak rate was). However, approximately 25% of patients reported more
recurrences in year 5 than year 1, evidence again of the substantial
interindividual differences in recurrence rates.
- Asymptomatic shedding of HSV can be demonstrated
by virus identification through culture or polymerase chain reaction (PCR). HSV
DNA can be detected four to five times more frequently by PCR than by culture., However, identification of virus by PCR may not be synonymous with infectivity.
The following data pertain to shedding demonstrated by isolation of infectious
- Asymptomatic shedding prevalence is greater in
women with HSV-2 genital infection than with HSV-1 (55% vs 29% during a median
follow-up of 105 days). A similar difference may exist in men.
- Asymptomatic shedding of HSV-2 is as common in
persons with symptomatic genital infection (while in between outbreaks) as in
those with asymptomatic genital infection-
- Asymptomatic shedding occurs on an average of 2%
of days for a mean duration of 1.5 days., HSV has been isolated
from vulva, cervicovaginal and rectal sites in women and from
penile and perianal skin, urethra and urine in men.
Prevention and Control
- Patients presenting with concerns about STIs
and/or prevention of pregnancy provide clinicians with an important opportunity
for instruction and encouragement about consistent safer-sex practices. Given
the increase in HSV-1 genital infection, likely due to orogenital sex (perhaps
as an alterative to genital intercourse), patients need also to be advised of
the inherent risk of genital herpes from such an activity.
- At the time of diagnosis of an STI, review and
monitor prevention practices. Identify barriers to prevention and the means to
- Condom use reduces transmission of genital HSV-2
from infected men to women by 50% and may reduce transmission from infected
women to men to a similar degree. However, condom effectiveness is
greatly limited by non-use and may also be limited because of the location of
lesions and the risk of transmission during orogenital sex. Other safer-sex
practices should be discussed.
- Valacyclovir 500 mg ingested daily by a patient
with genital HSV-2 infection has been shown to reduce transmission to a
susceptible heterosexual partner by 48%. The effect of condoms and suppressive
valacyclovir may be additive.
- Immunization with a glycoprotein D–adjuvanted
vaccine has been demonstrated to protect against acquisition of genital HSV
disease in women who were seronegative for both HSV-1 and -2, but not for those
who were seropositive for HSV-1. It had no protective efficacy in
men, regardless of serostatus. Protection against genital HSV disease was 74%,
and protection against infection (seroconversion plus symptomatic infection)
was 46%. Practitioners should be aware that such a vaccine may become available
for use in the next 5-10 years.
- A diagnostic lesion is a cluster of vesicles on
an erythematous background.
- First clinically evident episode in an HSV-antibody–negative
- Five characteristics:
- Extensive painful vesiculoulcerative genital
lesions, including exocervix.
- Systemic symptoms in 58-62% (fever, myalgia).
- Tender lymphadenopathy in 80%.
- Complications: 16-26% develop aseptic meningitis,
and 10-28% develop extragenital lesions.
- Protracted course: mean 16.5 (men) to 22.7
(women) days to resolve.
- First clinically evident episode in a person
who, by testing, is demonstrated to have pre-existing heterologous antibody.
Generally the range and severity of symptoms and signs of even the most severe
cases are less marked than in those with severe primary infection. This has
been attributed to a mitigating effect of pre-existing heterologous immunity in
attenuating the severity of disease.
- Compared to primary genital herpes, non-primary
infections are characterized by the following:
- Less extensive genital lesions.
- Systemic symptoms in only 16%.
- Complications uncommon: meningitis in 1% and
extragenital lesions in 8%.
- Duration less prolonged: mean 15.5 days.
- The first clinically evident episode in a person
with pre-existing homologous antibody (i.e. culture of HSV-2 from a first
outbreak in an individual with demonstrable HSV-2 antibody) may sometimes be
confused with a primary infection. This is because overlap occurs
in the frequency of local symptoms, fever and size of genital lesions between
those with recently acquired genital herpes and those, who, by serologic
testing, are determined to have acquired infection remotely but are now
experiencing a first outbreak.
- In one study, almost 10% of patients judged to
have a first-episode of genital herpes had serologic evidence of remotely
acquired HSV-2 infection, indicating that clinical differentiation of primary
genital infection and previously acquired infection can be difficult.
- Thus, typing of the virus isolate and
type-specific serologic testing are required to differentiate between the two
entities: primary/non-primary infection vs. a first lesion due to reactivation
of a (long) latent infection acquired previously (see Diagnosis section,
of recurrent disease
- Due to reactivation of latent sacral sensory
- Typically, localized small painful genital
lesions (mean lesion area 10% of that in primary genital herpes).
- Systemic symptoms in 5-12%.
- Prodromal symptoms in 43-53%, for an average of
- Mean duration of lesion 9.3-10.6 days.
collection and laboratory diagnosis
- Culture is the most common method currently used
in public health laboratories in Canada to confirm the clinical diagnosis of
HSV. It is sensitive (70% from ulcers, 94% from vesicles) and permits
identification of HSV type.
- PCR is four times more sensitive than HSV
culture and is 100% specific. However, at this time, PCR assays
have not yet replaced culture for routine diagnosis of genital herpes in public
health laboratories in Canada.
- The Tzanck smear demonstrating diagnostic
multinucleated giant cell is 40-68% as sensitive as culture, while direct
fluorescent antibody has a sensitivity of 56% compared to culture., Neither test can thus be relied on for laboratory confirmation of diagnosis.
- The antibody response to primary infection is
characterized by early appearance of IgM, followed subsequently by IgG
antibody. IgM antibody usually wanes within a few months of infection; therefore, the presence of IgM antibody is an indirect indication of “recent”
- A primary infection is confirmed by
demonstrating an absence of HSV antibody in the acute-phase sample and the
presence of antibody in the convalescent blood sample (i.e., seroconversion).
- Most individuals seroconvert within 3-6 weeks;
by 12 weeks, more than 70% will have seroconverted.,
- The advent of testing for type-specific antibody
will allow practitioners to establish a diagnosis of primary infection and
determine whether the infection is due to HSV-1 or -2. Such information will
also permit practitioners to counsel individuals with genital herpes and their
partners. Type-specific antibody is best detected by Western blot analysis,
although new commercial enzyme immunoassays with improved sensitivity and
specificity are available. Enzyme immunoassay test results need
not be routinely confirmed by Western blot analysis. At this time,
type-specific HSV antibody assays are available only in a few laboratories in
Canada (see Special Considerations section, below).
- During recurrent genital HSV infection, no
consistent HSV antibody changes occur. Specifically, IgM appears
inconsistently, and IgM titres also do not change between acute and
- Detection of HSV-2 antibody is considered to be
accurate for detecting silent genital HSV-2 infection, but detecting HSV-1
antibody is not useful in the same way, because asymptomatic HSV-1 orolabial
infection is common.
- Counselling is an important component in
management. Genital HSV infection is not curable, but its somatic and
psychological morbidity can be ameliorated by sensitive, empathetic,
knowledgeable counselling. Thus, all patients who have genital HSV infections
and their sexual partner(s) can likely benefit from learning about the chronic
aspects of the disease after the acute illness subsides. Explain the natural
history of the disease, with emphasis on the potential for recurrent episodes,
asymptomatic shedding and sexual transmission. Advise patients that antiviral
therapy for recurrent episodes may shorten the duration of lesions, and
suppressive antiviral therapy can ameliorate or prevent recurrent outbreaks,
with one drug having been demonstrated to reduce transmission.
- The most common psychological patient concerns
include the following:
- Fear of transmission.
- Fear of being judged or rejected by partner.
- Loneliness, depression and low self-esteem.
- Anxiety concerning potential effect on
- Patients need to inform their sex partner(s)
that they have genital herpes. It may be useful to have the partner receive
counselling concurrently for information and possible serologic testing for
HSV-1 and/or -2 antibody.
- Type-specific serologic testing for HSV-1 and/or
-2 antibody can demonstrate whether couples are discordant or concordant for
HSV-1 and/or -2 infection. Such information will be useful in counselling
couples about the risk of transmission of genital herpes infection.
- It should be emphasized that most transmission
of genital herpes occurs in the context of asymptomatic shedding. Therefore, emphasizing the use of condoms and suppressive antiviral drug
therapy is important for reducing the risk of transmission.
- Transmission of genital herpes is decreased by
- Avoidance of contacts with lesions during
obvious periods of viral shedding (prodrome to re-epithelialization) from
lesions. Advise patients that they should abstain from sexual activity from the
onset of prodromal symptoms until the lesions have completely healed.
- Condom use (see Prevention section,
- Daily suppressive antiviral therapy, which
reduces recurrent lesions, asymptomatic viral shedding and transmission.
- Assess patients with genital herpes for other
STIs and treat as needed.
- Discuss the risk of neonatal infection with all
patients, including men. Women who have genital herpes should be advised to
inform the health care providers who care for them during pregnancy about their
- Genital herpes increases the risk of
acquisition of HIV twofold.
- Treatment is recommended for clinically
- Analgesia and laxatives may be required. Urinary
retention may be an indication for hospitalization.
Table 1. Treatment for first episode
- For severe primary disease, IV acyclovir 5 mg/per kg infused over 60 minutes every 8 hours [A-l] is optimal,
with conversion to oral therapy when substantial improvement has occurred.
- Acyclovir 200
mg PO five times per day for 5-10 days [A-l]
- Famciclovir 250
mg PO tid for 5 days [A-l] ,
- Valacyclovir 1000 mg PO bid for 10 days [A-l]
- Acyclovir 400
mg PO tid for 7-10 days is recommended by the U.S. Centers for Disease
- Oral acyclovir,
famciclovir and valacyclovir are comparably efficacious.
- Acyclovir has been
initiated as late as 5-7 days after onset of symptoms with benefit;
famciclovir has been initiated only in patients with symptoms of fewer than 5
days’ duration and valacyclovir in those with fewer than 72 hours of symptoms.
- Topical acyclovir does
not alleviate systemic symptoms and should not be used.
Table 2. Treatment for recurrent episodes
- Valacyclovir 500 mg PO bid OR 1 g PO daily for 3 days [B-l]
- Famciclovir 125
mg PO bid for 5 days [B-l]
- Acyclovir 200
mg PO 5 times/day for 5 days [C-l]
- A shorter course of acyclovir 800 mg PO
tid for 2 days appears as efficacious as the approved 5-day regimen [B-l]
famciclovir and acyclovir are approved for treatment of recurrent genital
- To be effective, these
drugs need to be started as early as possible during the development of a
recurrent lesion — preferably fewer than 6 hours (famciclovir) to 12 hours
(valacyclovir) after the first symptoms appear. Patient-initiated therapy at
the onset of prodromal symptoms has been proven effective in a Canadian study. To achieve this end, patients should have medication on hand and be provided
with specific information on when to initiate therapy.
- Suppressive therapy is intended for patients
with frequently recurring genital herpes, generally for those with recurrences
at least every 2 months or 6 times per year. In such patients,
suppressive therapy is preferred to episode therapy and improves
quality of life.
- For individuals with fewer than 6 recurrences
per year or one every 2 months, episode therapy is recommended (see above).
However, suppressive therapy will probably be efficacious and may be considered
on a case-by-case basis.
Table 3. Suppressive therapy for non pregnant patients
- Acyclovir 200
mg PO three to five times daily OR 400 mg PO bid [A-l]–
- Famciclovir 250
mg PO bid [A-l],
- Valacyclovir 500 mg PO daily [A-l] (for patients with nine or fewer recurrences per
year) OR 1000 mg daily [A-l], (for patients with more than
nine recurrences per year)
- Acyclovir, famciclovir
and valacyclovir are approved for suppressive therapy in Canada.
- Based on controlled
trials, safety and efficacy data suggest that acyclovir, valacyclovir and
famciclovir can be administered for up to 1 year. –
Table 4. Suppressive therapy for pregnant patients
- Acyclovir 200
mg PO qid [A-l] ,
- Acyclovir 400
mg PO tid [A-l],
- Valacyclovir 500
mg PO bid [A-l]
- All regimens have been evaluated and shown to
be efficacious in reducing recurrent disease and the need for cesarean
- All regimens require initiation at 36 weeks
with termination at parturition [A-l] .-
- There have been no
studies of sufficient power to adequately assess whether suppressive antiviral
drug therapy in pregnancy reduces maternal-to-child transmission or neonatal
herpes per se.
- Suppressive acyclovir
and suppressive valacyclovir have been demonstrated to reduce recurrence rates,
as well as asymptomatic shedding, and thereby obviate the need for cesarean
section to prevent neonatal herpes.– Use of acyclovir
suppression does not eliminate the need to observe the neonate carefully for
possible HSV infection.
- Acyclovir &
valacyclovir safety has been evaluated in limited numbers of pregnant women in
controlled trials and these trials concluded that acyclovir and valacyclovir
treatment during pregnancy were not harmful to the fetus and did not result in
any significant increase in adverse events.,, Data from
1207 women reported to the Acyclovir Pregnancy Registry including results from
111 women treated with valacyclovir support the conclusions of these controlled
Table 5. Therapy for neonatal herpes
- Acyclovir 45–60 mg/kg/day IV in three equal 8-hourly infusions, each over
60 minutes for 14 to 21 days [A-l].
Note: Consultation with a colleague experienced in this area should be sought.
Consideration for Other STIs
- Having HSV can increase the risk of acquiring
and transmitting HIV. This increased risk needs to
be explained; HIV testing with pre- and post-test counselling should be
- Genital ulcers can also be caused by syphilis,
chancroid or lymphogranuloma venereum, and testing for these should be
- Testing for other STIs, including chlamydia and
gonorrhea, should be considered.
- Immunization for hepatitis B may be indicated.
- See Primary Care and Sexually Transmitted
- Discuss HPV vaccine with women as per the
recommendations outlined in the Canada Communicable Disease Report, Volume 33
ACS-2, (2007) National Advisory Committee on Immunization (NACI) statement
on Human papillomavirus vaccine.
Reporting and partner notification
- At the time of publication, genital HSV
infections were reportable by physicians to local public health authorities in New
Brunswick, Nova Scotia, Prince Edward Island and Newfoundland. Neonatal HSV
infections are reportable in some provinces only. Whether cases are to be
reported on suspicion or after laboratory confirmation also varies.
- Partner notification is not required as a public
health measure, in part because of the following:
- Most disease presents as recurrences.
- It is difficult to assess whether a contact has
ever had a primary genital infection.
- Patients with genital herpes should be
encouraged to inform their sexual partner(s) from the preceding 60 days prior
to symptom onset or date of diagnosis where asymptomatic to make them aware of
the risk of infection, if uninfected, and to aid diagnosis in a partner if the
disease does arise.
- Follow-up cultures are not indicated, except
when there are unusual recurrent symptoms or to determine in vitro
susceptibility when resistance is suspected as a cause of therapeutic failure.
- Supportive counselling is an important component
of managing patients with genital herpes.
- Recent epidemiologic work on risk factors for
neonatal herpes has demonstrated that the greatest risk factor for
neonatal HSV infection is new maternal genital HSV-1 or -2 infection without a
fully developed maternal immune response by the time of delivery, resulting in
an infant born without homologous transplacental HSV type-specific antibody.
Four of nine such infants developed neonatal HSV infection. On the other hand,
infants delivered vaginally by women with reactivation of genital herpes with
genital lesions or asymptomatic HSV genital virus shedding at parturition had a
2% risk of infection (2 of 92 cases). Cesarean delivery was shown definitively
to protect against neonatal transmission of HSV. Thus, the opportunity for
preventing neonatal HSV relates more to obviating maternal genital infection
late in pregnancy than to identifying women with known genital HSV infection.
That is, there is reason for reassurance of pregnant women with a history of
- Incidence in Canada for 2000-2003 inclusive is
5.85 per 100,000 live births; 62.5% of these infections were attributed to
HSV-1. From 55-80% are due to HSV-2.–
- Intrauterine infection accounts for 5% of
neonatal HSV infection, and postnatal infection (usually HSV-1) for 15%.–
- Clinically, neonatal infection is classified as
skin-eye-mouth (SEM), central nervous system (CNS) or disseminated infection.
Mortality is 0%, 15% and 47%, respectively, and abnormal development at 1 year is
2%, 70% and 25%, respectively.,, However, overlap occurs, and
up to 30% of babies with SEM initially will progress to CNS disease as well.
- In the Canadian study, 63.8% of cases had
localized (SEM) disease, while 34.5% had infection that disseminated to the CNS
or other organs.
- Vesicular skin lesions may not be observed in
17% with SEM, 32% with CNS and 39% of neonates with disseminated disease.
- Risk of neonatal infection:
- Is up to 50% if mother has primary genital HSV
infection with lesions at parturition. In approximately 70% of
cases the mother has no history of genital herpes.,
- Is from 2-8% when vaginal delivery occurs and
mother has a recurrent genital lesion or has asymptomatic genital HSV shedding
- Median incubation period is 4 days, with a range
of 1-28 days.,,
- Most neonatal herpes begins after a seemingly
healthy neonate has left hospital.
- Acyclovir oral therapy suppresses recurrent
genital disease and asymptomatic shedding and thereby has been shown to reduce
the need for cesarean delivery (see Treatment section, above).
offering HSV type-specific serum antibody testing
- Alberta Provincial Laboratory for Public Health,
- National Microbiology Laboratory, Public Health
Agency of Canada, Winnipeg, Manitoba.
- Regional Virology & Chlamydia Laboratory,
- Children’s Hospital of Eastern Ontario
Laboratory, Ottawa, Ontario.
- Warnex Inc., Montreal, Quebec.
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