Antiviral Treatment of First Episode Genital Herpes

Antiviral Treatment of Recurrent Genital Herpes

Management of Severe Disease

Non-Pharmacologic Interventions

Patient Counseling and Partner Notification

Prevention of Transmission

To provide recommendations on the management of adults with genital herpes in the United Kingdom

• To update the Sexually Transmitted Diseases Treatment Guidelines 2002 (MMWR 2002;51[No. RR-6])
• To assist physicians and other health-care providers in preventing and treating STDs

Adults in the United Kingdom

Patients with STDs characterized by genital ulcers

Physicians

Advanced Practice Nurses
Allied Health Personnel
Health Care Providers
Managed Care Organizations
Nurses
Physician Assistants
Physicians
Public Health Departments

First Episode Genital Herpes

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

Principles of Management of Genital Herpes

Antiviral chemotherapy offers clinical benefits to the majority of symptomatic patients and is the mainstay of management.

Systemic antiviral drugs can partially control the signs and symptoms of herpes episodes when used to treat first clinical episodes and recurrent episodes or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued.

Topical therapy with antiviral drugs offers minimal clinical benefit, and its use is discouraged.

First Clinical Episode of Genital Herpes

Many patients with first-episode herpes have mild clinical manifestations but later develop severe or prolonged symptoms. Therefore, patients with initial genital herpes should receive antiviral therapy.

Recommended Regimens*

• Acyclovir 400 mg orally three times a day for 7-10 days
  OR
• Acyclovir 200 mg orally five times a day for 7-10 days
  OR
• Famciclovir 250 mg orally three times a day for 7-10 days
  OR
• Valacyclovir 1 g orally twice a day for 7-10 days

*Treatment may be extended if healing is incomplete after 10 days of therapy.

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.

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)

Established HSV-2 Infection

The majority of patients with symptomatic, first-episode genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are less frequent after initial genital HSV-1 infection. Intermittent asymptomatic shedding occurs in persons with genital HSV-2 infection, even in those with longstanding or clinically silent infection. Antiviral therapy for recurrent genital herpes can be administered either episodically to ameliorate or shorten the duration of lesions or continuously as suppressive therapy to reduce the frequency of recurrences. Many persons, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed. Some persons might prefer suppressive therapy, which has the additional advantage of decreasing the risk of genital HSV-2 transmission to susceptible partners.

Suppressive Therapy for Recurrent Genital Herpes

Suppressive therapy reduces the frequency of genital herpes recurrences by 70%-80% in patients who have frequent recurrences (i.e., >6 recurrences per year), and many patients report no symptomatic outbreaks. Treatment also is effective in patients with less frequent recurrences. Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year. Quality of life frequently is improved in patients with frequent recurrences who receive suppressive, compared with episodic treatment.

The frequency of recurrent genital herpes outbreaks diminishes over time in many patients, and the patient's psychological adjustment to the disease might change. Therefore, periodically during suppressive treatment (e.g., once a year), providers should discuss the need to continue therapy with the patient.

Daily treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection. Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences. Suppressive antiviral therapy probably reduces transmission when used by persons who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes.

Recommended Regimens

• Acyclovir 400 mg orally twice a day
  OR
• Famciclovir 250 mg orally twice a day
  OR
• Valacyclovir 500 mg orally once a day
  OR
• Valacyclovir 1.0 gram orally once a day

Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens in patients who have very frequent recurrences (i.e., >10 episodes per year). Several studies have compared valacyclovir or famciclovir with acyclovir. The results of these studies suggest that valacyclovir and famciclovir are comparable to acyclovir in clinical outcome. Ease of administration and cost also are important considerations for prolonged treatment.

Episodic Therapy for Recurrent Genital Herpes

Effective episodic treatment of recurrent herpes requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks. The patient should be provided with a supply of drug or a prescription for the medication with instructions to initiate treatment immediately when symptoms begin.

Recommended Regimens

• Acyclovir 400 mg orally three times a day for 5 days
  OR
• Acyclovir 800 mg orally twice a day for 5 days
  OR
• Acyclovir 800 mg orally three times a day for 2 days
  OR
• Famciclovir 125 mg orally twice daily for 5 days
  OR
• Famciclovir 1000 mg orally twice daily for 1 day
  OR
• Valacyclovir 500 mg orally twice a day for 3 days
  OR
• Valacyclovir 1.0 g orally once a day for 5 days

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)

Severe Disease

IV acyclovir therapy should be provided for patients who have severe HSV disease or complications that necessitate hospitalization (e.g., disseminated infection, pneumonitis, or hepatitis) or CNS complications (e.g., meningitis or encephalitis). The recommended regimen is acyclovir 5-10 mg/kg body weight IV every 8 hours for 2-7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days total therapy.

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.

Recurrent Genital Herpes

• 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

No recommendations offered.

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

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 can 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.

Counseling

Counseling of infected persons and their sex partners is critical to management of genital herpes. The goal of counseling is to 1) help patients cope with the infection and 2) prevent sexual and perinatal transmission. Although initial counseling can be provided at the first visit, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides. Multiple resources, including websites (http://www.ashastd.org and http://www.ihmf.org) and printed materials are available to assist patients, their partners, and clinicians in counseling.

HSV-infected persons might express anxiety concerning genital herpes that does not reflect the actual clinical severity of their disease; the psychological impact of infection frequently is substantial. Common concerns regarding genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children. The misconception that HSV causes cancer should be dispelled. The psychological effect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecognized genital herpes appears small and transient.

The following recommendations apply to counseling of persons with HSV infection:

• Persons who have genital herpes should be educated concerning the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and the attendant risks of sexual transmission.
• Persons experiencing a first episode of genital herpes should be advised that suppressive therapy is available and is effective in preventing symptomatic recurrent episodes and that episodic therapy sometimes is useful in shortening the duration of recurrent episodes.
• All persons with genital HSV infection should be encouraged to inform their current sex partners that they have genital herpes and to inform future partners before initiating a sexual relationship.
• Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding is more frequent in genital HSV-2 infection than genital HSV-1 infection and is most frequent during the first 12 months after acquiring HSV-2.
• All persons with genital herpes should remain abstinent from sexual activity with uninfected partners when lesions or prodromal symptoms are present.
• The risk of HSV-2 sexual transmission can be decreased by the daily use of valacyclovir by the infected person.
• Recent studies indicate that latex condoms, when used consistently and correctly, can reduce the risk for genital herpes transmission.
• Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV acquisition exists.
• The risk for neonatal HSV infection should be explained to all persons, including men. Pregnant women and women of childbearing age who have genital herpes should inform their providers who care for them during pregnancy as well as those who will care for their newborn infant. Pregnant women who are not infected with HSV-2 should be advised to avoid intercourse during the third trimester with men who have genital herpes. Similarly, pregnant women who are not infected with HSV-1 should be counseled to avoid genital exposure to HSV-1 during the third trimester (e.g., oral sex with a partner with oral herpes and vaginal intercourse with a partner with genital HSV-1 infection).
• Asymptomatic persons diagnosed with HSV-2 infection by type-specific serologic testing should receive the same counseling messages as persons with symptomatic infection. In addition, such persons should be taught about the clinical manifestations of genital herpes.

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. Other antivirals may be effective but efficacy has not been proven in clinical trials.

Suppressive Therapy for Recurrent Genital Herpes

Daily treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection. Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences. Suppressive antiviral therapy probably reduces transmission when used by persons who have multiple partners (including men who have sex with men [MSM]) and by those who are HSV-2 seropositive without a history of genital herpes.

Counseling

• Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding is more frequent in genital HSV-2 infection than genital HSV-1 infection and is most frequent during the first 12 months after acquiring HSV-2.
• All persons with genital herpes should remain abstinent from sexual activity with uninfected partners when lesions or prodromal symptoms are present.
• The risk of HSV-2 sexual transmission can be decreased by the daily use of valacyclovir by the infected person.
• Recent studies indicate that latex condoms, when used consistently and correctly, can reduce the risk for genital herpes transmission.

• Appropriate diagnosis, prognosis, counselling, and management of genital herpes
• Prevention of morbidity (physical and psychological) associated with genital herpes and reduced transmission and prevalence

• Appropriate diagnosis, treatment, and follow-up of patients with genital ulcers
• Decreased transmission of syphilis and herpes simplex virus to infants and sexual partners
• Increased identification of HIV co-infection
• Improved quality of life

Subgroups Most Likely to Benefit

Sexually active patients of reproductive potential

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

Allergic and other adverse reactions to acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described previously.

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.

The type of supporting evidence is not specifically stated for each recommendation.

Throughout the 2006 guideline document, the evidence used as the basis for specific recommendations is discussed briefly. More comprehensive, annotated discussions of such evidence will appear in background papers that will be published in a supplement issue of the journal Clinical Infectious Diseases.