Anogenital Herpes 2014

Only one-third of individuals appear to develop symptoms at the time of acquisition of infection with HSV-2. Incubation of infection from acquisition to first clinical signs and symptoms in this minority of individuals ranges from 2 days to 2 weeks.

Infection may be primary or non-primary. Disease episodes may be initial or recurrent and symptomatic or asymptomatic. It is likely that the majority of infections are acquired subclinically.

Prior infection with HSV-1 modifies the clinical manifestations of first infection by HSV-2, usually making symptoms less severe.

After childhood, symptomatic primary infection with HSV-1 is equally likely to be acquired in the genital area or oral areas.

Although primary and initial genital herpes in the UK may be caused by HSV-1 or HSV-2, the majority of infections in adults are due to HSV-1 with the probability of this over HSV-2 being greater at younger age (women <50 years, men <35years).

Following primary infection, the virus becomes latent in local sensory ganglia, periodically reactivating to cause symptomatic lesions or asymptomatic, but infectious, viral shedding.

The median recurrence rate for genital herpes after a symptomatic first episode is 0.34 recurrences/month (i.e. approximately four recurrences per year) for HSV-2 and is four times more frequent than the recurrence rate for HSV-1. Recurrence rates decline over time in most individuals, although this pattern is variable.

The majority of individuals found to be seropositive for HSV-2 type-specific antibodies subsequently develop symptomatic lesions (once aware of the range of clinical manifestations of HSV-2). In some of these individuals, the number of days when virus is shed asymptomatically exceeds the number of days of symptomatic shedding associated with lesions. Virus can be shed asymptomatically from the external genitalia, the anorectum, the cervix, and urethra.

In HIV-positive HSV-2 seropositive individuals, both symptomatic and asymptomatic shedding are increased, especially in those with low CD4 counts and those who are also seropositive for HSV-1.

• 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 non-primary or recurrent disease.
• Systemic symptoms consist of fever and myalgia.
• Rarely, systemic symptoms may be the only evidence of infection.

• Blistering and ulceration of the external genitalia or perianal region (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% of patients.
• Recurrent outbreaks are limited to the infected dermatome.

• Superinfection of lesions with candida and streptococcal species (typically occurs in the second week of lesion progression).
• Autonomic neuropathy, resulting in urinary retention.
• Autoinoculation to fingers and adjacent skin e.g. on thighs. Autoinoculation into damaged and inflamed skin has been shown to occur in both acquisition and recurrent disease.
• Aseptic meningitis

• 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 presented to physicians at a university research clinic with genital symptoms received a correct diagnosis of GH. This reflects the fact that a significant proportion of infections due to herpes may present atypically.

• HSV is a significant cause of proctitis in MSM. A retrospective review in the USA found that 16% of MSM with proctitis had HSV detected by culture methods, and that 3% had herpes in addition to another rectal STI.
• An Australian study comparing pathogens causing infectious proctitis in HIV-positive and HIV-negative MSM found HSV proctitis more commonly in HIV-positive compared with HIV-negative MSM (HSV-1 was found in 14.2% HIV-positive and 6.5% HIV-negative MSM, and HSV-2 in 22% HIV-positive and 12.3% HIV-negative MSM). Only 32% of MSM with HSV-associated proctitis had visible external anal ulceration.

The confirmation and typing of the infection and its type, by direct detection of HSV in genital lesions, are essential for diagnosis, prognosis, counselling, and management (IV, C).

Methods should be used that directly demonstrate HSV in swabs taken from the base of the anogenital lesion or the rectal mucosa in the case of proctitis. MSM presenting with proctitis should have a rectal swab taken for the detection of HSV (1b, A).

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

HSV DNA detection by polymerase chain reaction (PCR) increases HSV detection rates by 11–71% 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.

Other nucleic acid amplification test (NAAT) methods have also shown similar results. NAATs are recommended as the preferred diagnostic method for genital herpes (Ib, A). In-house PCR assays must be appropriately validated before clinical use. NAATs methods are now regarded as the test of choice. Confirmatory testing of positive PCR samples is currently not considered necessary.

HSV culture is still used in some centres but will miss approximately 30% of PCR-positive samples (most significantly patients presenting with late or with mild recurrent disease). The specificity is nearly 100%, but is influenced by virus shedding, specimen quality, sample storage, and conditions of transport. The yield of culture at all stages of the infection is significantly reduced by delayed processing of the sample and lack of specimen refrigeration post-collection and during transport.

Testing for HSV type-specific antibodies can be used to diagnose HSV infection. The detection of HSV-1 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 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. Urine tests are inappropriate for the diagnosis of herpes. Assays should be used that detect antibodies against the antigenically unique components of glycoproteins gG1 and gG2 (III, 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 91–99% sensitivity and 92–98% specificity relative to Western blot in sexually active adults. For some widely available commercial assays sensitivity is very different for HSV-2 and HSV-1, and test performance may be markedly different for samples from some ethnic groups.

Caution is needed in interpreting serology results because even highly sensitive and specific assays have poor predictive values in low prevalence populations (Table 1). Local epidemiological data and patient demographic characteristics should guide testing and result interpretation (III, 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 (III, 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 (III, B):

  1. Recurrent genital disease of unknown cause

  2. Counselling patients with initial episodes of disease (to help identify recent or established infection in order to aid counselling), including pregnant women

  3. Investigating asymptomatic partners of patients with genital herpes, including women who are planning a pregnancy or are pregnant, or couples concerned about possible susceptibility to transmission in possibly discordant relationships.

• Saline bathing
• Analgesia
• Topical anaesthetic agents, e.g. 5% lidocaine (lignocaine) ointment may be useful to apply especially prior to micturition. Although the potential for sensitisation exists in the use of topical anaesthetic agents, lidocaine is a rare sensitiser and can be used safely in genital herpes in the form of gel or ointment

• Oral antiviral drugs are indicated within 5 days of the start of the episode, while new lesions are still forming, or if systemic symptoms persist.

Aciclovir, valaciclovir, and famciclovir all reduce the severity and duration of episodes (Ib, A).

• Antiviral therapy does not alter the natural history of the disease in that frequency or severity of subsequent recurrences remains unaltered.
• Topical agents are less effective than oral agents.
• Combining oral and topical treatment is of no additional benefit over oral treatment alone.
• Intravenous therapy is indicated only when the patient cannot swallow or tolerate oral medication because of vomiting.
• There are no comparative studies to show benefit from therapy longer than 5 days. However, it may still be prudent to review the patient after 5 days and continue therapy if new lesions are still appearing at this time, or if systemic symptoms are still present, or if complications have occurred.

Recommended regimens (all for 5 days):

Preferred regimens:

• Aciclovir 400 mg three times daily
• Valaciclovir 500 mg twice daily

Alternative regimens:

• Aciclovir 200 mg five times daily
• Famciclovir 250 mg three times daily

• Hospitalisation may be required for urinary retention, meningism, and severe constitutional symptoms.
• If catheterisation is required, consideration should be given as to whether a suprapubic approach offers better symptom control to the individual patient.

• Saline bathing
• Petroleum jelly (e.g. Vaseline)
• Analgesia
• 5% lidocaine (lignocaine) ointment

• Oral aciclovir, valaciclovir, and famciclovir reduce the duration and severity of recurrent GH.
• The reduction in duration is a median of 1–2 days.
• Head-to-head studies show no advantage of one therapy over another or the advantage of extended 5-day treatment over short-course therapy.
• Prodrugs (such as valaciclovir and famciclovir) offer simplified twice-a-day dosing.
• Aborted lesions have been documented in up to a third of patients with early treatment.
• . Patient-initiated treatment started early in an episode is most likely to be effective, as treatment prior to the development of papules is of greatest benefit.
• Short-course therapies offer more convenient and cost-effective strategies for managing GH episodically and should be regarded as first-line options.

Short-course therapies:

• Aciclovir 800 mg three times daily for 2 days
• Famciclovir 1 g bd for 1 day
• Valaciclovir 500 mg bd for 3 days

Alternative 5-day treatment regimens:

• Aciclovir 200 mg five times daily
• Aciclovir 400 mg three times daily for 3–5 days
• Valaciclovir 500 mg twice daily
• Famciclovir 125 mg twice daily

• Patients who have taken part in trials of suppressive therapy have had to have at least six recurrences per annum. Such patients have fewer or no episodes on suppressive therapy (1b, 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.
• Patients suffering from psychological morbidity for who the diagnosis causes significant anxiety may benefit from suppressive therapy.
• Patient safety and resistance data for long-term suppressive therapy with aciclovir now extends to over 20 years of continuous surveillance (III, B).

This confirms that aciclovir is an extremely safe compound requiring no monitoring in previously well patients and only a dose adjustment in those with severe renal disease.

Recommended regimens (1b, 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 (Table 2).
• Suppressive therapy should be discontinued after a maximum of a year to reassess recurrence frequency. The minimum period of assessment should include two recurrences since a recurrence often occurs when ending suppression. Patients who continue to have unacceptably high rates of recurrence or problematic disease may restart treatment. (IV, C).
• Short courses of suppressive therapy may be helpful for some patients (IV, C). Clinicians need to note that the full suppressive effect is usually only obtained 5 days into treatment.

In view of HSV being a common cause of proctitis in MSM, clinicians should consider empirical treatment for HSV in the presence of symptomatic proctitis. Antiviral treatment is as for genital herpes.