Herpes Simplex, Mucocutaneous

Background

Herpes simplex virus (HSV) types 1 and 2 cause both primary and recurrent oral and genital disease. HSV usually appears as a vesicular eruption of the mucous membranes of the oral or perioral area, vulva, perianal skin, rectum, and occasionally the inguinal or buttock areas. The eruption develops into tender or painful ulcerated lesions that frequently are covered with a clear yellow crust. In some patients, however, the typical painful vesicular or ulcerative lesions may be absent. Persons with HIV disease and low CD4 cell counts have more frequent recurrences of HSV and more extensive ulcerations than do HIV-uninfected people. Persistent HSV eruption (lasting >1 month) is an AIDS-indicator diagnosis. HSV facilitates HIV transmission.

S: Subjective

The patient may complain of eruption of red, painful vesicles or ulcers ("fever blisters") with or without an exudate in the mouth, on the lips (and occasionally in nares), on the genitals, or in the perianal area. The patient may complain of burning, tingling, or itching before eruption of the lesions. In the genital area, symptoms may be nonspecific without any eruption of lesions; most HSV type 1 and 2 infections are asymptomatic, yet virus can still be shed.

The vesicles will rupture and ulcerate, generally crusting over and healing in approximately 7-14 days. The lesions may be pruritic and are often painful. As immunosuppression progresses, the lesions may recur more frequently, grow larger or coalesce, and become chronic and nonhealing.

Perform a history, asking the patient about the symptoms described above, duration, associated symptoms, and history of oral or genital HSV infection.

O: Objective

Look for grouped vesicular or ulcerative lesions on an erythematous base on the mouth, anus, or external genitals, or ones that are visible on speculum or anoscopic examination. When immunosuppression is severe, lesions may coalesce into large, painful, and nonhealing ulcerations that spread to the skin of the thighs, lips, face, or perirectal region. These chronic erosive lesions may be confused with a chronic bacterial infection or decubitus ulcer, and should prompt consideration of acyclovir-resistant HSV infection. Recurrent lesions may start atypically, first appearing as a fissure, pustule, or abrasion.

A: Assessment

A partial differential diagnosis includes the following:

• Oral: Oral aphthous ulcers
• Genital: Chancroid, syphilis, cytomegalovirus, candidiasis, drug-related eruption, trauma

P: Plan

Diagnostic Evaluation

A clinical diagnosis of HSV can be made on the basis of the patient's symptoms and clinical appearance only if vesicles and constitutional symptoms are present, but symptoms and signs may be variable, and primary syphilis always must be ruled out. Also, HSV-1 (rather than HSV-2) is increasingly the cause of initial episodes of anogenital herpes. For these reasons, current guidelines recommend laboratory testing to establish the diagnosis of HSV and to determine its type.

For cell culture or polymerase chain reaction (PCR), obtain a specimen from a freshly opened vesicle or the base of an ulcer for culture confirmation. Note that lesions that are >72 hours old or are beginning to resolve may not show HSV in culture. Tzanck smears are not sensitive or specific.

PCR is more sensitive for detection of herpes DNA in ulcerative lesions, but is more expensive to perform and is less widely available than viral culture. If virologic test results are positive, typing should be performed to determine the type of HSV. Negative results do not rule out the possibility of HSV infection.

If cultures are negative, a sample can be taken from a fresh lesion for another culture or for PCR. In addition, type-specific serologic tests may be useful in the evaluation of symptomatic patients in whom a diagnosis of genital HSV is not clear. Current guidelines also recommend that serologic testing be considered for HIV-infected individuals, for MSM, and for those who present for sexually transmitted disease (STD) evaluation if there is no history of past genital HSV diagnosis. Glycoprotein G (gG)-based serologic assays are recommended, as older assays do not reliably differentiate HSV-1 antibody from HSV-2 antibody.

In any patient who presents with genital, anal, or oral ulceration, even if the suspicion of HSV is high, syphilis serologic testing (rapid plasma reagin [RPR], Venereal Disease Research Laboratory [VDRL], enzyme immunoassay [EIA], or cytopathic effect [CPE] inhibitory assay) should be done (see chapter Syphilis).

Treatment

Empiric treatment for new-onset suspicious lesions, especially if symptoms are significant, often is initiated in the absence of laboratory confirmation. Note: Dosage must be adjusted for patients with renal impairment.

First Clinical Episode

• Acyclovir 400 mg PO TID for 7-10 days
• Acyclovir 200 mg PO 5 times a day for 7-10 days
• Famciclovir 250 mg PO TID for 7-10 days
• Valacyclovir 1,000 mg PO BID for 7-10 days

Established HSV Infection

Suppressive therapy

Consider suppressive therapy for patients with frequent or severe recurrences and those with HSV-2. Acyclovir dosage may need to be increased to 800 mg BID or TID for individuals whose HSV episodes are not adequately suppressed by 400 mg BID. Treatment may be continued indefinitely. Note that the extent to which suppressive therapy reduces the risk of transmission of HSV in HIV-infected persons is unknown. Effective antiretroviral therapy (ART) also may reduce the frequency of HSV outbreaks.

• Acyclovir 400-800 mg PO BID to TID
• Valacyclovir 500 mg PO BID
• Famciclovir 500 mg PO BID

Episodic therapy (for greatest efficacy, start treatment within 1 day of lesion onset or during prodrome)

• Acyclovir 400 mg PO TID for 5-10 days
• Valacyclovir 1,000 mg PO BID for 5-10 days
• Famciclovir 500 mg PO BID for 5-10 days

Note: Short-course episodic therapy (1-3 days) usually is not recommended for persons with HIV infection.

Symptomatic treatment helps the healing of lesions but does not prevent recurrences. Large, extensive ulcers may need to be treated for a longer period of time.

Severe disease

Treat initially with acyclovir 5-10 mg/kg IV Q8H (10 mg/kg for encephalitis) for 2-7 days, followed by oral HSV antiviral for a total of 10 days.

Acyclovir-resistant HSV

The diagnosis of acyclovir-resistant HSV should be suspected if lesions fail to respond to 7-10 days of standard therapy and should be confirmed with culture and sensitivities. Cross-resistance to valacyclovir and ganciclovir will be present, and cross-resistance to famciclovir is likely. The usual alternative treatment is foscarnet (40 mg/kg IV Q8H); other possibilities include IV cidofovir, topical imiquimod, and topical cidofovir. An HIV specialist should be consulted.

HSV During Pregnancy

Acyclovir appears to be safe and effective for use by pregnant women and remains the drug of choice. Few data are available on the use of valacyclovir and famciclovir during pregnancy.

It is important to avoid peripartum transmission of HSV. For women with recurrent or new genital HSV late in pregnancy, obstetric or infectious disease specialists should be consulted. All women should be evaluated carefully for symptoms and signs of genital HSV at delivery.

Patient Education

• Patients should be told that HSV has no cure, but treatment can decrease symptoms and recurrences. Treatment also has been shown to decrease shedding and HSV transmission in HIV-uninfected discordant couples, but it has not been studied in HIV-infected couples. Outbreaks and viral shedding may occur at intervals for the rest of their lives but frequency generally decreases with age of infection.
• HSV may be spread through kissing (if mouth or lips are infected) and sexual contact (oral, anal, or vaginal). Most HSV is transmitted when no genital lesions are present, so it is important that patients inform their sex partners of their herpes infection before sexual activity. Patients must avoid all sexual contact when lesions are visible, because a high volume of virus is present at those times. Correct use of condoms at each sexual encounter offers the best chance of reducing HSV transmission.
• All patients with genital HSV should be encouraged to inform their partners.
• Episodic treatment is most effective when taken early in the outbreak, so patients not taking suppressive therapy should keep medication on hand and start treatment at the first signs of a prodrome or eruption.
• Genital HSV in a pregnant woman around the time of delivery can cause severe illness in the newborn. Women should inform their obstetrician and pediatrician if they have a history of HSV or are exposed to or infected with HSV during pregnancy. Pregnant women who do not have HSV should avoid sexual practices that facilitate HSV transmission in the third trimester with partners who have HSV, and men who have HSV should avoid sexual practices that facilitate HSV transmission with pregnant women in their third trimester who do not have HSV.

References

• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.
• Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2010. MMWR 2010 Dec 17; 59 (No. RR-12):1-110.
• Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based review. Arch Intern Med. 2008 Jun 9;168(11):1137-44.
• Lingappa JR, Celum C. Clinical and therapeutic issues for herpes simplex virus-2 and HIV co-infection. Drugs. 2007;67(2):155-74.
• Strick LB, Wald A, Celum C. Management of herpes simplex virus type 2 infection in HIV type 1-infected persons. Clin Infect Dis. 2006 Aug 1;43(3):347-56.
• Wald A, Langenberg AG, Krantz E, et al. The relationship between condom use and herpes simplex virus acquisition. Ann Intern Med. 2005 Nov 15;143(10):707-13.