• 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.
• 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

• Another useful website for patient information is provided by the International Herpes Alliance: 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.

For information about availability, see the "Availability of Companion Documents" and "Patient Resources" fields below.

Electronic copies: Available in Portable Document Format (PDF) from the British Association of Sexual Health and HIV Web Site.

Auditable outcome measures are provided in the original guideline document.

Guidelines represented on the NGC Web site are submitted by guideline developers, and are screened solely to determine that they meet the NGC Inclusion Criteria which may be found at http://www.guideline.gov/about/inclusion.aspx .

NGC, AHRQ, and its contractor ECRI Institute make no warranties concerning the content or clinical efficacy or effectiveness of the clinical practice guidelines and related materials represented on this site. Moreover, the views and opinions of developers or authors of guidelines represented on this site do not necessarily state or reflect those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or hosting of guidelines in NGC may not be used for advertising or commercial endorsement purposes.

Readers with questions regarding guideline content are directed to contact the guideline developer.