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## Complete Summary

#### GUIDELINE TITLE

2007 national guideline for the management of genital herpes.

#### BIBLIOGRAPHIC SOURCE(S)

Clinical Effectiveness Group. 2007 national guideline for the management
of genital herpes. London (UK): British Association for Sexual Health
and HIV (BASHH); 2007. 26 p. \[107 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previously released version: Association for
Genitourinary Medicine (AGUM), Medical Society for the Study of Venereal
Disease (MSSVD). 2002 national guideline for the management of genital
herpes. London: Association for Genitourinary Medicine (AGUM), Medical
Society for the Study of Venereal Disease (MSSVD); 2002. Various p.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   Genital herpes infection (herpes simplex virus type 1 \[HSV-1\] or 2
    \[HSV-2\] infection)

-   Pregnancy

-   Human immunodeficiency virus (HIV) infection

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Counseling\
Diagnosis\
Evaluation\
Management\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Infectious Diseases\
Obstetrics and Gynecology\
Urology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To provide recommendations on the management of adults with genital
herpes in the United Kingdom, including pregnant women and individuals
co-infected with human immunodeficiency virus (HIV)

#### TARGET POPULATION

Adults in the United Kingdom including pregnant women and individuals
co-infected with human immunodeficiency virus (HIV)

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis**

1.  Direct detection of herpes simplex virus (HSV) in swabs taken from
    the base of genital lesions

2.  HSV detection by polymerase chain reaction (PCR) (preferred method)
    or isolation in cell culture

3.  Serological testing for HSV type-specific antibodies by commercial
    tests or Western blot

**Treatment/Management**

1.  First episode genital herpes

    -   General advice: saline bathing, analgesia, and topical
        anaesthetic agents

    -   Treatment with antiviral drugs: aciclovir, valaciclovir, or
        famciclovir

    -   Management of complications, including hospitalisation and
        catheterisation

2.  Recurrent genital herpes

    -   General advice: saline bathing, Vaseline, analgesia, 5%
        lidocaine ointment

    -   Episodic and suppressive antiviral treatment with aciclovir,
        valaciclovir, or famciclovir

3.  Prevention of transmission

    -   Condom use

    -   Suppression of symptomatic and asymptomatic viral shedding with
        acyclovir, famciclovir, or valaciclovir

4.  Counselling, patient education and support, and partner notification
    issues

5.  Management of herpes in pregnancy

    -   Referral to a Genitourinary Physician

    -   Treatment with aciclovir for first episode and daily suppressive
        aciclovir from 36 weeks gestation, for first and second
        trimester acquisition of herpes

    -   Continuous aciclovir in the last 4 weeks of pregnancy for third
        trimester acquisition of herpes

    -   Consideration of aciclovir suppressive therapy beginning at 36
        weeks gestation for recurrent herpes

    -   Vaginal delivery or offer of Caesarean section, as indicated

    -   Intrapartum aciclovir treatment of mother during vaginal
        delivery and subsequently the neonate, as indicated

    -   Patient education/counseling to prevent maternal acquisition of
        HSV in pregnancy

6.  Management of genital herpes in people with human immunodeficiency
    virus (HIV)

    -   Treatment of immune reconstitution inflammatory syndrome
        (IRIS)-associated HSV with topical cidofovir

    -   Treatment of first episode genital herpes with oral aciclovir,
        valaciclovir, or famciclovir

    -   Repeat viral culture with susceptibility testing and increased
        dose of HSV therapy, if needed

    -   Treatment of severe cases of first episode herpes with
        intravenous aciclovir

    -   Optimization of highly active antiretroviral therapy (HAART) to
        reduce HSV recurrence

    -   Suppressive antiviral treatment with aciclovir, famciclovir, or
        valaciclover

    -   Treatment of drug-resistant herpes in people with HIV with
        topical foscarnet cream and cidofovir gel or with intravenous
        foscarnet or cidofovir (administered with oral probenecid and
        adequate pre-hydration)

#### MAJOR OUTCOMES CONSIDERED

-   Herpes simplex virus (HSV) detection rates

-   Sensitivity and specificity of HSV tests

-   Rate of healing of HSV lesions

-   Severity of HSV episodes

-   Rate of viral shedding (symptomatic and asymptomatic)

-   HSV recurrence rate

-   HSV transmission rate, including transmission from mother to neonate

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

This review was updated by searching PubMed from 1999-2007 for
publications in English using the search terms/Mesh headings: Diagnosis:
\"Herpes genitalis\", \"Herpes simplex diagnosis. Neonatal herpes:
\"Neonatal herpes\", \"pregnancy complications -- infectious\", \"herpes
near pregnancy\" free text. A search of the Cochrane Library was also
searched using the MeSH terms: \"randomized controlled trials\",
\"Genital Herpes\", \"herpes genitalis\".

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Levels of Evidence**:

**Ia**

-   Evidence obtained from meta-analysis of randomised controlled trials

**Ib**

-   Evidence obtained from at least one randomised controlled trial

**IIa**

-   Evidence obtained from at least one well designed controlled study
    without randomisation

**IIb**

-   Evidence obtained from at least one other type of well designed
    quasi-experimental study

**III**

-   Evidence obtained from well designed non-experimental descriptive
    studies such as comparative studies, correlation studies, and case
    control studies

**IV**

-   Evidence obtained from expert committee reports or opinions and/or
    clinical experience of respected authorities

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The current guideline has been developed by the Herpes Simplex Advisory
Panel, which is a special interest group of British Association of
Sexual Health and HIV (BASHH). The Panel incorporates specialist
clinicians, virologists, health advisers, nurses, clinical psychologist
and a representative from the Herpes Viruses Association (a self help
organisation). The Process was overseen by the Clinical Effectiveness
Group of BASHH. This is the second revision of the guideline first
written in 1999.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Grading of Recommendations**

**A (Evidence Levels Ia, Ib)**

-   Requires at least one randomised controlled trial as part of the
    body of literature of overall good quality and consistency
    addressing the specific recommendation.

**B (Evidence Levels IIa, IIb, III)**

-   Requires availability of well conducted clinical studies but no
    randomised clinical trials on the topic of recommendation.

**C (Evidence Level IV)**

-   Requires evidence from expert committee reports or opinions and/or
    clinical experience of respected authorities.

-   Indicates absence of directly applicable studies of good quality.

#### COST ANALYSIS

A formal cost analysis was not performed, and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The draft guideline was placed on the British Association of Sexual
Health and HIV (BASHH) website for a 3 month consultation period.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Levels of evidence (**I-IV**) and grades of recommendation (**A-C**) are
defined at the end of the \"Major Recommendations\" field.

**Clinical Features**

**Symptoms**

-   The patient may be asymptomatic, and the disease unrecognised.

-   Local symptoms consist of painful ulceration, dysuria, vaginal or
    urethral discharge.

-   Systemic symptoms are much more common in primary than in initial or
    recurrent disease.

-   Systemic symptoms consist of fever and myalgia.

-   Rarely, systemic symptoms may be the only evidence of infection.

**Signs**

-   Blistering and ulceration of the external genitalia (+/-
    cervix/rectum).

-   Tender inguinal lymphadenitis, usually bilateral.

-   In first episodes, lesions and lymphadenitis are usually bilateral.
    In recurrent disease, it is usual for lesions to affect favoured
    sites. They may alternate between sides but are usually unilateral
    for each episode. Lymphadenitis occurs in around 30%.

**Complications**

-   Autonomic neuropathy, resulting in urinary retention

-   Autoinoculation to fingers and adjacent skin e.g., on thighs

-   Aseptic meningitis

**Atypical Genital Herpes**

-   The lesions of recurrent episodes may be small, and may resemble
    non-specific erythema, erosions or fissures.

-   In the United States, only about 20% of those patients who present
    to physicians with genital symptoms receive a correct diagnosis of
    genital herpes.

**Diagnosis**

For a detailed discussion of diagnostic methods for genital herpes
please refer to the \"Sexually Transmitted Infection Screening and
Testing Guidelines\" (2006 edition) produced by the Screening Guidelines
Steering Committee of the British Association of Sexual Health and HIV
(BASHH) Clinical Effectiveness Group. The diagnostic tests outlined
below may not be available in all settings because of local facilities
or cost.

**Virus Detection and Characterisation**

-   The confirmation and characterisation of the infection and its type,
    by direct detection of herpes simplex virus (HSV) in genital
    lesions, are essential for diagnosis, prognosis, counselling, and
    management (**Level of Evidence IV, Grade of Recommendation C**).

-   Methods should be used that directly demonstrate HSV in swabs taken
    from the base of the genital lesion. (**Level of Evidence 1b, Grade
    of Recommendation A**).

-   Virus typing to differentiate between HSV-1 and HSV-2 should be
    obtained in all patients with newly diagnosed genital herpes
    (**Level of Evidence III, Grade of Recommendation B**).

-   HSV isolation in cell culture is the current routine diagnostic
    method in the United Kingdom (UK). Virus culture is slow,
    labour-intensive, and expensive. Specificity is virtually 100%, but
    levels of virus shedding, quality of specimens, and sample storage
    and transport conditions influence sensitivity. Delayed sample
    processing and lack of specimen refrigeration after collection and
    during transport significantly reduce the yield of virus culture at
    all stages of the infection.

-   HSV DNA detection by polymerase chain reaction (PCR) increases HSV
    detection rates by 11% to 71% compared with virus culture. PCR-based
    methods allow less stringent conditions for sample storage and
    transport than virus culture and new real-time PCR assays are rapid
    and highly specific. Real-time PCR is recommended as the preferred
    diagnostic method for genital herpes (**Level of Evidence Ib, Grade
    of Recommendation A**). PCR assays must be appropriately validated
    before clinical use and their availability should be discussed with
    service providers.

**Serology**

-   Testing for HSV type-specific antibodies can be used to diagnose HSV
    infection. The detection of HSV-1 immunoglobulin G (IgG) or HSV-2
    IgG or both, in a single serum sample represents HSV infection with
    HSV at some time. It is difficult to say whether the infection is
    recent as immunoglobulin M (IgM) detection is unreliable and avidity
    studies are not commonly available. Collection of serum samples a
    few weeks apart can be used to show seroconversion and, hence,
    recent primary infection. HSV-2 antibodies are indicative of genital
    herpes. HSV-1 antibodies do not differentiate between genital and
    oropharyngeal infection.

-   Many commercial tests for HSV antibodies are not type-specific and
    are of no value in the management of genital herpes. Assays should
    be used that detect antibodies against the antigenically unique
    glycoproteins, glycoprotein G1 (gG1) and glycoprotein G2 (gG2)
    (**Level of Evidence III, Grade of Recommendation B**).

-   Western blot is the diagnostic gold-standard, but it is not
    commercially available. Several commercial assays, as well as
    validated in-house methods, are available which show 91% to 99%
    sensitivity and 92% to 98% specificity relative to Western blot in
    sexually active adults.

-   Caution is needed in interpreting serology results because even
    highly sensitive and specific assays have poor predictive values in
    low prevalence populations (see Table 1 in the original guideline
    document). Local epidemiological data and patient demographic
    characteristics should guide testing and result interpretation
    (**Level of Evidence III, Grade of Recommendation B**).

-   In patients with a low likelihood of genital herpes, a positive
    HSV-2 antibody result should be confirmed in a repeat sample or by a
    different assay (**Level of Evidence III, Grade of Recommendation
    B**).

-   Type-specific immune responses usually take several weeks to
    develop. The median time to antibody detection may vary between
    different assays. False negative results may be obtained early after
    infection, requiring follow-up samples to demonstrate
    seroconversion.

-   The value of routine screening of all genitourinary medicine clinic
    attendees or antenatal patients and their partners for HSV
    antibodies remains to be established. Serology may be helpful in the
    following situations (**Level of Evidence III, Grade of
    Recommendation B**):

    -   Recurrent genital disease of unknown cause

    -   Counselling patients with initial episodes of disease, including
        pregnant women

    -   Investigating asymptomatic partners of patients with genital
        herpes, including pregnant women

**Management**

**First Episode Genital Herpes**

*General Advice*

-   Saline bathing

-   Analgesia

-   Topical anaesthetic agents e.g., 5% lidocaine (lignocaine) ointment
    may be useful to apply especially prior to micturition but should be
    used with caution because of the risk of potential sensitization.

*Antiviral Drugs*

-   Oral antiviral drugs are indicated within 5 days of the start of the
    episode and while new lesions are still forming.

-   Aciclovir, valaciclovir, and famciclovir all reduce the severity and
    duration of episodes (**Level of Evidence Ib, Grade of
    Recommendation A**).

-   Antiviral therapy does not alter the natural history of the disease.

-   Topical agents are less effective than oral agents.

-   Combined oral and topical treatment is of no benefit.

-   Intravenous therapy is indicated only when the patient cannot
    swallow or tolerate oral medication because of vomiting.

-   There is no evidence for benefit from courses longer than five days.
    However, it may be prudent to review the patient after 5 days and
    continue therapy if new lesions are still appearing at this time.

*Recommended Regimens* (All for Five Days)

-   Aciclovir 200 mg five times daily

-   Aciclovir 400 mg three times daily

-   Valaciclovir 500 mg twice daily

-   Famciclovir 250 mg three times daily

*Management of Complications*

-   Hospitalisation may be required for urinary retention, meningism,
    and severe constitutional symptoms.

-   If catheterisation is required, suprapubic catheterisation is
    preferred to prevent theoretical risk of ascending infection, to
    reduce the pain associated with the procedure, to allow normal
    micturition to be restored without multiple removals and
    recatheterisations (**Level of Evidence IV, Grade of Recommendation
    C**)

**Recurrent Genital Herpes**

-   Recurrences are self-limiting and generally cause minor symptoms.

-   Management decisions should be made in partnership with the patient.
    Strategies include:

    -   Supportive therapy only

    -   Episodic antiviral treatments

    -   Suppressive antiviral therapy

-   The best strategy for managing an individual patient may change over
    time according to recurrence frequency, symptom severity, and
    relationship status.

-   General advice (**Level of Evidence IV, Grade of Recommendation C**)

    -   Saline bathing

    -   Vaseline

    -   Analgesia

    -   5% lidocaine (lignocaine) ointment

**Episodic Antiviral Treatment (Level of Evidence Ia, Grade of
Recommendation A)**

-   Oral aciclovir, valaciclovir, and famciclovir reduce the duration
    (by median of 1 to 2 days) and severity of recurrent genital herpes.

-   Patient initiated treatment started early in an episode is most
    likely to be effective.

-   Recommended regimens (all for five days)

    -   Aciclovir 200 mg five times daily

    -   Aciclovir 400 mg three times daily for 3 to 5 days

    -   Valaciclovir 500 mg twice daily

    -   Famciclovir 125 mg twice daily

-   Short course therapies

    -   Aciclovir 800 mg three times daily for 2 days

    -   Famciclovir 1 g twice a day (bd) for one day

    -   Valaciclovir 500 mg bd for 3 days

**Suppressive Antiviral Therapy**

-   Patients who have taken part in trials of suppressive therapy have
    had at least six recurrences per annum. Such patients have fewer or
    no episodes on suppressive therapy (**Level of Evidence Ib, Grade of
    Recommendation A**). Patients with lower rates of recurrence will
    probably also have fewer recurrences with treatment.

-   Patients should be given full information on the advantages and
    disadvantages of suppressive therapy. The decision to start
    suppressive therapy is a subjective one, balancing the frequency of
    recurrence with the cost and inconvenience of treatment.

-   Patient safety and resistance data for long-term suppressive therapy
    with aciclovir now extends to over 18 years of continuous
    surveillance (**Level of Evidence III, Grade of Recommendation B**).

-   Recommended regimens (**Level of Evidence Ib, Grade of
    Recommendation A**):

    -   Aciclovir 400 mg twice daily

    -   Aciclovir 200 mg four times daily

    -   Famciclovir 250 mg twice daily

    -   Valaciclovir 500 mg once daily

-   If breakthrough recurrences occur on standard treatment, the daily
    dosage should be increased e.g., aciclovir 400 mg three times daily.

-   Choice of treatment depends on patient compliance and cost (see
    Table 3 in the original guideline document).

-   Suppressive therapy should be discontinued after a maximum of a year
    to reassess recurrence frequency. The minimum period of assessment
    should include two recurrences. Patients who continue to have
    unacceptably high rates of recurrence may restart treatment.
    (**Level of Evidence IV, Grade of Recommendation C**).

-   Short courses of suppressive therapy may be helpful for some
    patients (**Level of Evidence IV, Grade of Recommendation C**).

**Asymptomatic Viral Shedding**

-   Occurs in individuals with genital HSV-1 and those with genital
    HSV-2.

-   Occurs most commonly in patients with genital HSV-2 infection in the
    first year after infection

    -   In individuals with frequent symptomatic recurrences

    -   Is an important cause of transmission

    -   May be reduced by aciclovir 400 mg twice daily (**Level of
        Evidence 1b, Grade of Recommendation A**)

**Prevention of Transmission**

-   Condoms may be partially effective in preventing acquisition of HSV,
    especially in preventing transmission from infected males to their
    female sex partners. The efficacy of male condoms in preventing
    transmission from infected females to uninfected male partners has
    not been demonstrated, and the efficacy of female condoms to reduce
    HSV transmission during intercourse has not been assessed.

-   Aciclovir, famciclovir, and valaciclovir all suppress symptomatic
    and asymptomatic viral shedding. These drugs have been shown in
    clinical trials to reduce asymptomatic HSV shedding by about 80% to
    90%. Although the threshold for infection from asymptomatic shedding
    has not been established, small studies have shown that valaciclovir
    appears to suppress asymptomatic shedding better than famciclovir.
    Aciclovir (400 mg twice daily) has been shown to suppress
    asymptomatic shedding at least as well as valaciclovir (1000 mg
    daily).

-   Suppressive antiviral therapy with valaciclovir 500 mg once daily
    reduces the rate of acquisition of HSV-2 infection and clinically
    symptomatic genital herpes in serodiscordant couples. In a
    randomised trial involving 1,484 patients treated for 8 months, 0.5%
    valaciclovir recipients developed symptomatic infection compared
    with 2.2% of placebo recipients, and 1.6% compared with 3.2%
    acquired HSV-2 infection. Although valaciclovir reduced the risk of
    acquiring symptomatic infection by 75%, approximately 60 people
    needed to be treated to prevent one transmission. Other antivirals
    may be effective but efficacy has not been proven in clinical
    trials.

**Counselling**

-   Diagnosis often causes considerable distress. Most people with
    recurrences adjust over time but antiviral treatment can probably
    reduce anxiety, assist adjustment and improve quality of life
    (**Level of Evidence II, Grade of Recommendation B**).

-   Counselling should be as practical as possible and address
    particular personal situations; issues for someone in a long-term
    relationship are likely to be different from those for someone
    seeking a partner.

-   Disclosure is often a difficult issue for patients but is more
    likely to happen in the context of an on-going relationship.

-   Failure by the patient to control everyday stresses does not affect
    recurrences.

-   For most patients one or two counselling sessions with an invitation
    to return in case of difficulty should be enough.

-   Patients who have failed to adjust to the diagnosis after a year
    should be considered for more intensive counselling interventions.

-   Counselling should cover:

    -   Natural history

    -   The use of antiviral drugs for symptom control; current
        uncertainties about impact on infectivity should be discussed

    -   Discussion of the risks of transmission by sexual contact
        related to the actual situation of the patient

    -   Reassurance regarding transmission by fomites and
        autoinoculation after the first infection is over

    -   Abstinence from sexual contact during lesional recurrences or
        prodromes

    -   Transmission may occur as a result of asymptomatic viral
        shedding

    -   Seropositive patients with unrecognised recurrences can be
        taught to recognise symptomatic episodes after counselling and
        this may prevent onward transmission

    -   The possible benefit of condoms in reducing transmission,
        emphasizing that their use cannot completely prevent
        transmission

    -   Pregnancy issues for both men and women (see below)

**Patient Support**

-   The distressing nature of symptoms and the stigma associated with
    HSV infection, as with other conditions, often results in impaired
    patient retention of information given by clinical staff.

-   The Family Planning Association (FPA) produces a range of leaflets
    on sexual health for the National Health Service (NHS). Their
    leaflet on genital herpes provides comprehensive patient information
    based on British Association of Sexual Health and HIV (BASHH)
    guidelines and be purchased or viewed as a non-printable PDF file on
    the [FPA Web
    site](http://www.fpa.org.uk/attachments/published/144/PDF Genital herpes October 2006.pdf).

-   Patients frequently benefit from talking to the Herpes Viruses
    Association helpline 0845 123 2305 - weekdays

> Office phone line to order patient materials 020 7607 9661
>
> Email: <info@herpes.org.uk>
>
> Website: [www.herpes.org.uk](http://www.herpes.org.uk/)

-   Another useful website for patient information is provided by the
    International Herpes Alliance:
    [www.herpesalliance.org](http://www.herpesalliance.org/)

**Partner Notification**

-   Is an effective way of detecting individuals with unrecognised
    disease.

-   May clarify whether a partner is infected or not (utilising
    type-specific antibody testing if necessary). This may help to
    relieve anxiety about transmission or reinforce the need to reduce
    the risk of transmission.

-   May help with the counselling process.

-   Awareness of the diagnosis in a partner or ex-partner may prevent
    further onward transmission.

**Herpes Vaccines**

There are no vaccines currently approved for prevention of genital
herpes although trials are ongoing. Published studies using the HSV-2
glycoprotein-D adjuvant vaccine have shown limited efficacy in
preventing clinical disease and only in women who were seronegative for
both HSV-1 and HSV-2 at baseline. The guideline authors do not support
the use of unauthorized or unlicensed vaccines outside of clinical
trials.

**Management of Herpes in Pregnancy**

Guidelines for genital herpes in pregnancy are categorised into
management of first episodes and recurrent episodes. Accurate clinical
classification is difficult. Viral isolation and typing and the testing
of paired sera (if a booking specimen is available) may be helpful.
Referral to a Genitourinary Physician for advice on management of women
with suspected genital herpes is recommended.

**First Episode Genital Herpes**

*First and Second Trimester Acquisition*

-   First episode genital herpes has been associated with first
    trimester miscarriage; however, there is no conclusive evidence that
    it causes developmental abnormality if the pregnancy continues. The
    occurrence of first episode genital herpes is not considered an
    indication for termination of pregnancy. An anomaly scan may be
    considered at 20 to 22 weeks gestation where this is not routine.

-   Management should be in line with the clinical condition with the
    use of either oral or intravenous aciclovir.

-   Although aciclovir is not licensed for use in pregnancy, there is
    substantial clinical experience supporting its safety.

-   Vaginal delivery should be anticipated (**Level of Evidence IV,
    Grade of Recommendation C**).

-   Daily suppressive aciclovir from 36 weeks gestation may be
    considered for women who experience a first-episode of genital
    herpes in order to reduce the likelihood of HSV lesions at term, and
    the offer of Caesarean section (CS) delivery (**Level of Evidence
    1b, Grade of Recommendation B**). There are sound arguments for
    using aciclovir 400 mg three times a day (tid) because of the
    altered pharmacokinetics of the drug in late pregnancy.

*Third Trimester Acquisition* (**Level of Evidence IV, Grade of
Recommendation C**)

-   CS for the prevention of neonatal herpes has not been evaluated in
    randomised controlled trials.

-   CS should be offered to all women presenting with first-episode
    genital herpes lesions at the time of delivery, or within 6 weeks of
    the expected date of delivery or onset of labour. However CS may not
    be of benefit in reducing transmission for women presenting with
    ruptured membranes for greater than four hours. In all these cases
    the paediatricians should be informed (**Grade of Recommendation
    B**).

-   Continuous aciclovir in the last 4 weeks of pregnancy reduces the
    risk of both clinical recurrence at term and delivery by CS (**Level
    of Evidence Ib, Grade of Recommendation B**).

-   If vaginal delivery is unavoidable or where the mother opts for a
    vaginal birth, prolonged rupture of membranes should be avoided and
    invasive procedures should not be used. Intravenous aciclovir given
    intrapartum to the mother and subsequently to the neonate may be
    considered. The paediatricians should be informed.

**Recurrent Genital Herpes (Level of Evidence III, Grade of
Recommendation B)**

-   Antiviral treatment is rarely indicated for treatment of recurrent
    episodes of genital herpes during pregnancy.

-   Symptomatic recurrences during the third trimester are likely to be
    brief; vaginal delivery is appropriate if no lesions are present at
    delivery.

-   If there are no genital lesions at delivery, CS to prevent neonatal
    herpes should not be performed.

-   Cultures during late gestation to predict viral shedding at term are
    not indicated.

-   Sequential cultures during late pregnancy do not predict viral
    shedding at term.

-   The benefits of obtaining specimens for culture at delivery to
    identify women who are asymptomatically shedding HSV are unproven.

-   Aciclovir suppressive treatment from 36 weeks gestation may be
    considered.

-   A systematic review of five randomised clinical trials involving a
    total enrolment of 799 patients has shown that aciclovir prophylaxis
    beginning at 36 weeks gestation was effective in reducing clinical
    HSV recurrences at the time of delivery (OR 0.25; 95% confidence
    interval 0.15, 0.40, reducing CS deliveries for clinical recurrence
    of genital herpes (OR 0.30; 95% CI 0.13, 0.67, reducing total HSV
    detection at delivery (OR 0.11; 95% CI 0.04, 0.31, and asymptomatic
    shedding at delivery (OR 0.09; 95% CI 0.02; 0.39). (**Evidence level
    IA, Grade of Recommendation A**).

-   The use of aciclovir prophylaxis may also be cost-effective.

-   Two randomized controlled trials of valaciclovir prophylaxis to
    prevent recurrent genital herpes at term were reported in 2006. The
    first involved a total of 112 enrolled patients who were HSV-2
    seropositive. Valaciclovir use in comparison with placebo reduced
    the number of women with clinical recurrences between the time of
    randomization and delivery (RR 0.40, 95% CI 0.2, 0.9). However, the
    proportions of women with viral shedding within 7 days of delivery
    (10.4% vs. 12.0%) and with clinical HSV lesions at delivery (5.3%
    vs. 14.6%) were not statistically different. The second larger study
    enrolled a total of 350 women with a history of genital herpes, of
    whom 82% had recurrent genital herpes. The use of valaciclovir as
    compared with placebo was associated with a significantly reduced
    proportion of women requiring CS delivery (4% vs. 13%, p = 0.009),
    and with positive HSV cultures (2% vs. 9%, p\<0.02).

**Genital Lesions at Onset of Labour (Level of Evidence III, Grade of
Recommendation B)**

-   Caesarean section (CS) should be considered for women with recurrent
    genital herpes lesions at the onset of labour. Recurrent genital
    herpes at any other time during pregnancy is not an indication for
    delivery by CS. The risks of vaginal delivery for the fetus are
    small and must be set against risks to the mother of CS.

-   Clinical diagnosis of genital herpes at the time of labour
    correlates relatively poorly with HSV detection from genital sites
    or lesions by culture or PCR and fails to identify asymptomatic
    women who have HSV in their genital secretions at the time of labor.
    Thus, the presence of genital lesions has a sensitivity for HSV
    detection of 37% by culture and 41% by PCR.

-   For women with a history of recurrent genital herpes, who would opt
    for Caesarean delivery if HSV lesions were to be detected at the
    onset of labour, daily suppressive aciclovir given from 36 weeks
    gestation until delivery may be given to reduce the likelihood of
    HSV lesions at term (**Grade of Recommendation A**).

**Prevention of Acquisition of Infection (Level of Evidence IV, Grade of
Recommendation C)**

-   Maternal risk of HSV acquisition in pregnancy varies geographically
    and local epidemiological surveillance should guide strategy for
    prevention.

-   Women may be asked about or may volunteer at their first antenatal
    visit a history that they or their male partner have had genital
    herpes.

-   Women who report a history of genital herpes can be reassured that
    the risk of transmission to the neonate is very small, even if
    genital lesions are present at delivery.

-   Recurrences during pregnancy pose no threat to the pregnancy or
    well-being of the foetus.

-   Identifying women susceptible to acquiring genital herpes in
    pregnancy by means of type-specific screening for HSV antibodies in
    pregnancy has not been shown to be cost-effective and is not
    currently indicated in the UK.

-   Female partners of men with genital herpes, who themselves give no
    history of genital herpes, should be advised about reducing their
    risk of acquiring this infection. Women may reduce their risk of
    acquiring herpes during pregnancy and of subsequent transmission to
    the neonate by using condoms consistently, especially the third
    trimester, and abstaining from sexual intercourse during
    recurrences. Women should avoid receptive oro-genital contact if
    their partner has oro-labial herpes.

-   All women, not just those with a history of genital herpes, should
    undergo careful vulval inspection at the onset of labour to look for
    clinical signs of Herpes simplex infection.

-   Neonatal herpes may occur as a result of nosocomial or
    community-acquired infection. Mothers, staff, and other
    relatives/friends with active HSV infection, such as orolabial
    herpes or herpetic whitlow, should avoid direct contact between
    lesions and the neonate.

**Management of Herpes in People with Human Immunodeficiency Virus
(HIV)**

-   There is epidemiological synergy between HSV and HIV infections.
    Herpes simplex infections activate HIV replication and may
    facilitate onward HIV transmission to sexual partners. Suppressive
    treatment of HSV-2 infection with valaciclovir has been shown to
    reduce genital HIV shedding in women. In addition, both prevalent
    and incident HSV 2 infections are associated with an increased risk
    of HIV acquisition.

-   Genital herpes is the most common sexually transmitted infection
    (STI) in HIV positive heterosexuals in the UK. The natural history
    of genital herpes in untreated people with HIV (PWHIV) is
    significantly different from that in HIV-negative individuals. The
    most important risk factor for herpes reactivation is the degree of
    HIV associated immunosuppression.

-   Standard systemic antiviral drugs, as used to treat genital herpes
    in HIV-uninfected patients, have been shown to successfully treat
    genital herpes PWHIV. Resistance to antiherpes drugs is more common
    in those with HIV co-infection and is associated with treatment
    failure of genital herpes.

-   Much of the evidence on herpes management in PWHIV comes from
    studies performed before the era of combination antiretroviral
    therapy; prospective studies performed early in the epidemic showed
    that clinical lesions might be persistent and progressive in those
    with HIV. Genital herpes, including chronic erosive lesions may
    occur as a manifestation of the immune reconstitution inflammatory
    syndrome (IRIS) following combination antiretroviral therapy. HSV
    associated IRIS may be unresponsive to previously effective
    anti-herpes viral therapy in the absence of increased antiviral
    resistance. Management is difficult but topical cidofovir may be
    effective.

**First Episode Genital Herpes**

-   In the absence of HIV therapy, primary genital herpes may be severe
    and prolonged with risk of progressive, multifocal and coalescing
    mucocutaneous anogenital lesions. Moreover, serious and potentially
    life-threatening systemic complications, such as fulminant
    hepatitis, pneumonia, neurological disease and disseminated
    infection have been reported.

-   Prompt initiation of therapy is recommended if herpes is suspected
    clinically. If new lesions are still forming after 3 to 5 days, a
    repeat viral culture with susceptibility testing should be performed
    and the dose of HSV therapy increased. Definitive studies in PWHIV
    are lacking.

    -   Recommended regimens. (**Level of Evidence IIb, Grade of
        Recommendation B**)

        -   Aciclovir 400 mg five times daily for 7 to 10 days

        -   Valaciclovir 1 g twice daily for 10 days

        -   Famciclovir 250 mg to 750 mg twice daily for 10 days

-   In severe cases, initiation of therapy with aciclovir 5 mg/kg body
    weight to 10 mg/kg body weight intravenous every 8 hours may be
    necessary. Induction therapy should be continued intravenously for 2
    to 7 days, or until clinical improvement, and followed by oral
    antiviral therapy to complete a minimum of 10 days total treatment.
    (**Level of Evidence IV, Grade of Recommendation C**).

**Recurrent Genital Herpes**

Both clinical and subclinical reactivations of genital herpes are more
frequent in PWHIV and may lead to persistent and progressive anogenital
mucocutaneous lesions, especially with cluster of differentiation 4
(CD4) cell counts less than 50 per cubic millimetre. Optimising the
control of HIV replication with combination antiretroviral therapy is of
fundamental importance for the management of recurrent genital herpes.
Highly Active Retroviral Therapy (HAART) will reduce the frequency of
clinical recurrences but has less effect upon asymptomatic viral
shedding. Thereafter, specific antiviral drugs can be used for either
episodic or suppressive treatment.

**Episodic Treatment**

In controlled trials in HSV and HIV co-infected persons, episodic
treatment with the following regimens was found to be effective.

-   Famciclovir 500 mg twice daily for 7 days was as effective as
    aciclovir 400 mg five times daily for 7 days (**Level of Evidence
    Ib, Grade of Recommendation A**).

-   Valaciclovir 1 g twice daily for 5 days was no less effective than
    aciclovir 200 mg five times daily for 5 days (**Level of Evidence
    Ib, Grade of Recommendation A**).

-   Valaciclovir 500 mg twice daily for 3 days was equivalent to the
    same regimen given for 5 days (**Level of Evidence Ib, Grade of
    Recommendation A**).

The following drug regimens are recommended for episodic treatment
(**Level of Evidence IV, Grade of Recommendation C**):

-   Aciclovir 400 mg orally three times daily for 5 to 10 days

-   Famciclovir 500 mg twice daily for 5 to 10 days

-   Valaciclovir 1 g twice daily for 5 to 10 days

**Suppressive Treatment**

The efficacy of suppressive antiviral therapy in PWHIV appears to be
less than in HIV-negative people. It is recommended that intermittent
cessation of suppressive antiviral therapy for genital herpes should
occur, especially in those in whom there is also adequate inhibition of
HIV replication and rising CD4 cell counts. In some PWHIV with less
frequent outbreaks of genital herpes, episodic treatment may be
substituted. In others, where the pre-treatment pattern of recurrences
resumes, suppressive treatment may need to restart (**Level of Evidence
IV, Grade of Recommendation C**).

Recommended drug regimens for daily suppressive treatment:

-   Aciclovir 400 to 800 mg orally twice to three times a day

-   Famciclovir 500 mg orally twice a day

-   Valaciclovir 500 mg orally twice a day

**Drug Resistant Genital Herpes**

-   In prospective studies, aciclovir-resistant strains have been found
    in around 5% to 7% isolates from genital herpes lesions in
    HIV-infected persons. Aciclovir resistance is confirmed if isolates
    require aciclovir concentrations \>1 mg/l to 3 mg/l for inhibition.

-   Aciclovir resistance is most commonly related to a mutation in the
    gene encoding HSV thymidine kinase (TK), which is responsible for
    initial phosphorylation of aciclovir to its active form, resulting
    in TK that either has reduced affinity for aciclovir or is not
    synthesised. TK-deficient strains are of reduced pathogenicity in
    immunocompetent individuals but may cause serious local and systemic
    disease in severely immunocompromised individuals. They appear less
    likely to be associated with the development of latency; hence,
    subsequent clinical reactivations of genital herpes are often caused
    by aciclovir-sensitive isolates. Partially resistant strains may
    sometimes be successfully treated with high dose intravenous
    aciclovir and other nucleoside analogues but fully
    aciclovir-resistant strains are resistant to valaciclovir and
    ganciclovir, and the majority are resistant to famciclovir.
    TK-deficient strains are susceptible to foscarnet and cidofovir
    which do not depend upon TK but which inhibit viral DNA polymerase.

-   Antiviral susceptibility testing for HSV is not currently available
    in the UK. Clinical response to antiviral therapy is used to guide
    decisions. Advice from a clinical virologist about appropriate drug
    dosages and duration may be sought when clinical resistance is
    suspected.

-   Both topical 1% foscarnet cream and 1% cidofovir gel have been shown
    to produce significant benefits in lesion healing, pain reduction
    and virological effect in drug resistant herpes in PWHIV. (**Level
    of Evidence Ib, Grade of Recommendation A**)

-   There is limited evidence to support the use of topical
    trifluorothymidine alone or in combination with interferon-alpha
    (**Level of Evidence IIb, Grade of Recommendation B**).

-   Systemic therapy with either foscarnet or cidofovir is generally
    preferred to treat drug resistant herpes in those with HIV. There is
    evidence for:

    -   Foscarnet 40 mg/kg body weight intravenous every 8 hours until
        clinical resolution. (**Level of Evidence Ib, Grade of
        Recommendation A**).

    -   Cidofovir 5 mg/kg body weight weekly intravenous infusion
        (**Level of Evidence IV**)

-   Cidofovir is administered with oral probenecid and adequate
    pre-hydration to reduce the risk of nephrotoxicity. It may be
    effective in aciclovir-resistant infections that are also resistant
    to foscarnet. Initial therapy at 5 mg/kg is given weekly, as an
    infusion over one hour, for two weeks. Systemic treatment should
    continue until clinical resolution is attained.

-   Alternating courses of treatment with aciclovir and cidofovir for
    subsequent recurrences has been advocated as a strategy that may
    reduce the development of cidofovir-resistant strains. The efficacy,
    safety, and durability of the therapeutic response of these agents
    have yet to be determined in prospective controlled trials.

**Definitions**:

**Levels of Evidence**

**Ia**

-   Evidence obtained from meta-analysis of randomised controlled trials

**Ib**

-   Evidence obtained from at least one randomised controlled trial

**IIa**

-   Evidence obtained from at least one well designed controlled study
    without randomisation

**IIb**

-   Evidence obtained from at least one other type of well designed
    quasi-experimental study

**III**

-   Evidence obtained from well designed non-experimental descriptive
    studies such as comparative studies, correlation studies, and case
    control studies

**IV**

-   Evidence obtained from expert committee reports or opinions and/or
    clinical experience of respected authorities

**Grading of Recommendations**

**A (Evidence Levels Ia, Ib)**

-   Requires at least one randomised controlled trial as part of the
    body of literature of overall good quality and consistency
    addressing the specific recommendation.

**B (Evidence Levels IIa, IIb, III)**

-   Requires availability of well conducted clinical studies but no
    randomised clinical trials on the topic of recommendation.

**C (Evidence Level IV)**

-   Requires evidence from expert committee reports or opinions and/or
    clinical experience of respected authorities.

-   Indicates absence of directly applicable studies of good quality.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is graded and identified for select
recommendations (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Appropriate diagnosis, prognosis, counselling, and management of
    genital herpes

-   Prevention of morbidity (physical and psychological) associated with
    genital herpes and reduced transmission and prevalence

#### POTENTIAL HARMS

Topical anaesthetic agents should be used with caution because of the
risk of potential sensitization.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Audit Criteria/Indicators

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness

#### IOM DOMAIN

Effectiveness\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Clinical Effectiveness Group. 2007 national guideline for the management
of genital herpes. London (UK): British Association for Sexual Health
and HIV (BASHH); 2007. 26 p. \[107 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

1999 Aug (revised 2007)

#### GUIDELINE DEVELOPER(S)

British Association for Sexual Health and HIV - Medical Specialty
Society

#### SOURCE(S) OF FUNDING

No specific or external funding was sought or provided in the
development of this guideline.

#### GUIDELINE COMMITTEE

Clinical Effectiveness Group (CEG)

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*The Herpes Simplex Advisory Panel Members*: Prof. George Kinghorn
(*Chair*); Dr Simon Barton; Ms Jayne Bickford; Dr David Brown; Dr
Frances Cowan; Dr Jane Deayton; Dr John Green; Dr Eva Jungmann; Dr Chris
Maple; Ms Marian Nicholson; Dr Nigel O\'Farrell; Dr Raj Patel; Dr Anne
Scoular

*Clinical Effectiveness Group (CEG) Members*: Keith Radcliffe
(Chairman); Imtyaz Ahmed-Jushuf; Dr David Daniels; Dr Mark FitzGerald;
Dr Gill McCarthy; Dr Neil Lazaro; Dr Guy Rooney

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The Herpes Simplex Advisory Panel is a special interest group of British
Association of Sexual Health and HIV (BASHH). It has received
unrestricted educational grants from pharmaceutical companies. Some
Panel members have participated in clinical trials supported by and/or
have received travel grants to attend educational meetings and/or have
acted as consultants for various pharmaceutical companies including
GlaxoSmithKline (GSK), Novartis, and Aventis.

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previously released version: Association for
Genitourinary Medicine (AGUM), Medical Society for the Study of Venereal
Disease (MSSVD). 2002 national guideline for the management of genital
herpes. London: Association for Genitourinary Medicine (AGUM), Medical
Society for the Study of Venereal Disease (MSSVD); 2002. Various p.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[British Association of Sexual Health and HIV Web
Site](http://www.bashh.org/documents/115/115.pdf).

#### AVAILABILITY OF COMPANION DOCUMENTS

Auditable outcome measures are provided in the [original guideline
document](http://www.bashh.org/documents/115/115.pdf).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on June 15, 2000. The information was
verified by the guideline developer on October 13, 2000. This summary
was updated by ECRI on June 24, 2002. This summary was updated by ECRI
Institute on June 16, 2008. The updated information was verified by the
guideline developer on August 13, 2008.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developers and/or BMJ Publishing Group\'s copyright
restrictions. Reproduction and use of this guideline is permitted
provided that (a) the original content is not changed or edited; and,
(b) any content derived from the original guideline is acknowledged as
that of the author(s) and responsible organizations.

Readers wishing to download and reproduce material for purposes other
than personal study or education should contact BMJPG to seek permission
first. Contact: BMJ Publishing Group, BMA House, Tavistock Square, WC1H
9JR, UK.

### DISCLAIMER

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