Genital herpes is a chronic, lifelong viral infection. Two types of HSV can cause genital herpes: HSV-1 and HSV-2. Most cases of recurrent genital herpes are caused by HSV-2, and 11.9% of persons aged 14–49 years are estimated to be infected in the United States (436). However, an increasing proportion of anogenital herpetic infections have been attributed to HSV-1, which is especially prominent among young women and MSM (186,437,438).
The majority of persons infected with HSV-2 have not had the condition diagnosed, many of whom have mild or unrecognized infections but shed virus intermittently in the anogenital area. Consequently, most genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs. Management of genital HSV should address the chronic nature of the infection rather than focusing solely on treating acute episodes of genital lesions.
Clinical diagnosis of genital herpes can be difficult because the self-limited, recurrent, painful, and vesicular or ulcerative lesions classically associated with HSV are absent in many infected persons at the time of clinical evaluation. If genital lesions are present, clinical diagnosis of genital herpes should be confirmed by type-specific virologic testing from the lesion by NAAT or culture (186). Recurrences and subclinical shedding are much more frequent for HSV-2 genital herpes infection than for HSV-1 genital herpes (439,440). Therefore, prognosis and counseling depend on which HSV type is present. Type-specific serologic tests can be used to aid in the diagnosis of HSV infection in the absence of genital lesions. Both type-specific virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care to persons with or at risk for STIs. HSV-2 genital herpes infection increases the risk for acquiring HIV twofold to threefold; therefore, all persons with genital herpes should be tested for HIV (441).
HSV NAAT assays are the most sensitive tests because they detect HSV from genital ulcers or other mucocutaneous lesions; these tests are increasingly available (442–444). Although multiple FDA-cleared assays exist for HSV detection, these tests vary in sensitivity from 90.9% to 100%; however, they are considered highly specific (445–447). PCR is also the test of choice for diagnosing HSV infections affecting the central nervous system (CNS) and systemic infections (e.g., meningitis, encephalitis, and neonatal herpes). HSV PCR of the blood should not be performed to diagnose genital herpes infection, except in cases in which concern exists for disseminated infection (e.g., hepatitis). In certain settings, viral culture is the only available virologic test. The sensitivity of viral culture is low, especially for recurrent lesions, and decreases rapidly as lesions begin to heal (443,448). Viral culture isolates and PCR amplicons should be typed to determine whether HSV-1 or HSV-2 is causing the infection. Failure to detect HSV by NAAT or culture, especially in the presence of older lesions or the absence of active lesions, does not indicate an absence of HSV infection because viral shedding is intermittent. Similarly, random or blind genital swabs in the absence of lesions should not be used to diagnose genital HSV infection because sensitivity is low, and a negative result does not exclude the presence of HSV infection.
Cytologic detection of cellular changes associated with HSV infection is an insensitive and nonspecific method of diagnosing genital lesions (i.e., Tzanck preparation) and therefore should not be relied on. Although a direct immunofluorescence assay using fluorescein-labeled monoclonal antibodies is also available for detecting HSV antigen from genital specimens, this assay lacks sensitivity and is not recommended (449).
Type-Specific Serologic Tests
Both type-specific and type-common antibodies to HSV develop during the first weeks after infection and persist indefinitely. The majority of available, accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (gG2) (HSV-2) and glycoprotein G1 (gG1) (HSV-1). Type-common antibody tests do not distinguish between HSV-1 and HSV-2 infection; therefore, type-specific serologic assays should be requested (450–452).
Both laboratory-based assays and POC tests that provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit are available. The sensitivity of glycoprotein G type-specific tests for detecting HSV-2 antibody varies from 80% to 98%; false-negative results might be more frequent at early stages of infection (451,453,454). Therefore, in cases of recent suspected HSV-2 acquisition, repeat type-specific antibody testing 12 weeks after the presumed time of acquisition is indicated. The most commonly used test, HerpeSelect HSV-2 enzyme immunoassay (EIA), often is falsely positive at low index values (1.1–3.0) (457–457). One study reported an overall specificity of 57.4%, with a specificity of 39.8% for index values of 1.1–2.9 (458). Because of the poor specificity of commercially available type-specific EIAs, particularly with low index values (<3.0), a confirmatory test (Biokit or Western blot) with a second method should be performed before test interpretation. Use of confirmatory testing with the Biokit or the Western blot assays have been reported to improve accuracy of HSV-2 serologic testing (459). The HerpeSelect HSV-2 immunoblot should not be used for confirmation because it uses the same antigen as the HSV-2 EIA. If confirmatory tests are unavailable, patients should be counseled about the limitations of available testing before obtaining serologic tests, and health care providers should be aware that false-positive results occur. Immunoglobulin M (IgM) testing for HSV-1 or HSV-2 is not useful because IgM tests are not type specific and might be positive during recurrent genital or oral episodes of herpes (460). Therefore, HSV IgM testing is not recommended.
Because approximately all HSV-2 infections are sexually acquired, presence of type-specific HSV-2 antibody implies anogenital infection. In this instance, education and counseling for persons with genital HSV infections should be provided. The presence of HSV-1 antibody alone is more difficult to interpret. HSV-1 serologic testing does not distinguish between oral and genital infection and typically should not be performed for diagnosing genital HSV-1 infection. Persons with HSV-1 antibodies often have oral HSV infection acquired during childhood, which might be asymptomatic. Lack of symptoms in a person who is HSV-1 seropositive does not distinguish anogenital from orolabial or cutaneous infection, and, regardless of site of infection, these persons remain at risk for acquiring HSV-2. In addition, HSV-1 serologic testing has low sensitivity for detection of HSV-1 antibody (458). However, acquisition of HSV-1 genital herpes is increasing, and HSV-1 genital herpes also can be asymptomatic (437–439,461,462). Diagnosis of HSV-1 infection is confirmed by virologic tests from genital lesions.
Type-specific HSV-2 serologic assays for diagnosing HSV-2 are useful in the following scenarios: recurrent or atypical genital symptoms or lesions with a negative HSV PCR or culture result, clinical diagnosis of genital herpes without laboratory confirmation, and a patient’s partner has genital herpes. HSV-2 serologic screening among the general population is not recommended. Patients who are at higher risk for infection (e.g., those presenting for an STI evaluation, especially for persons with ≥10 lifetime sex partners, and persons with HIV infection) might need to be assessed for a history of genital herpes symptoms, followed by type-specific HSV serologic assays to diagnose genital herpes for those with genital symptoms.
Genital Herpes Management
Antiviral medication offers clinical benefits to symptomatic patients and is the mainstay of management. The goals for use of antiviral medications to treat genital herpes infection are to treat or prevent symptomatic genital herpes recurrences and improve quality of life and suppress the virus to prevent transmission to sexual partners. Counseling regarding the natural history of genital herpes, risks for sexual and perinatal transmission, and methods for reducing transmission is also integral to clinical management.
Systemic antiviral drugs can partially control the signs and symptoms of genital herpes when used to treat first clinical 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. Randomized trials have indicated that three FDA-approved antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir (463–471). Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration, allowing for less frequent dosing than acyclovir. Famciclovir also has high oral bioavailability. Topical therapy with antiviral drugs offers minimal clinical benefit and is discouraged.
First Clinical Episode of Genital Herpes
Newly acquired genital herpes can cause a prolonged clinical illness with severe genital ulcerations and neurologic involvement. Even persons with first-episode herpes who have mild clinical manifestations initially can experience severe or prolonged symptoms during recurrent infection. Therefore, all patients with first episodes of genital herpes should receive antiviral therapy.
Acyclovir† 400 mg orally 3 times/day for 7–10 days
Famciclovir 250 mg orally 3 times/day for 7–10 days
Valacyclovir 1 gm orally 2 times/day for 7–10 days
* Treatment can be extended if healing is incomplete after 10 days of therapy.
†Acyclovir 200 mg orally five times/day is also effective but is not recommended because of the frequency of dosing.
Recurrent HSV-2 Genital Herpes
Almost all persons with symptomatic first-episode HSV-2 genital herpes subsequently experience recurrent episodes of genital lesions. Intermittent asymptomatic shedding occurs among persons with HSV-2 genital herpes infection, even those with longstanding clinically silent infection. Antiviral therapy for recurrent genital herpes can be administered either as suppressive therapy to reduce the frequency of recurrences or episodically to ameliorate or shorten the duration of lesions. Certain persons, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed. Many persons prefer suppressive therapy, which has the additional advantage of decreasing the risk for transmitting HSV-2 genital herpes to susceptible partners (472,473).
Suppressive Therapy for Recurrent HSV-2 Genital Herpes
Suppressive therapy reduces frequency of genital herpes recurrences by 70%–80% among patients who have frequent recurrences (469–472). Persons receiving such therapy often report having experienced no symptomatic outbreaks. Suppressive therapy also is effective for patients with less frequent recurrences. Long-term safety and efficacy have been documented among patients receiving daily acyclovir, valacyclovir, and famciclovir (474). Quality of life is improved for many patients with frequent recurrences who receive suppressive therapy rather than episodic treatment (475). Providers should discuss with patients on an annual basis whether they want to continue suppressive therapy because frequency of genital HSV-2 recurrence diminishes over time for many persons. However, neither treatment discontinuation nor laboratory monitoring is necessary because adverse events and development of HSV antiviral resistance related to long-term antiviral use are uncommon.
Treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission for discordant heterosexual couples in which a partner has a history of genital HSV-2 infection (473). Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy for preventing transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences. Suppressive antiviral therapy for persons with a history of symptomatic genital herpes also is likely to reduce transmission when used by those who have multiple partners. HSV-2 seropositive persons without a history of symptomatic genital herpes have a 50% decreased risk for genital shedding, compared with those with symptomatic genital herpes (476). No data are available regarding efficacy of suppressive therapy for preventing HSV-2 transmission among discordant couples in which a partner has a history of asymptomatic HSV-2 infection identified by a positive HSV-2 serologic test. Among HSV-2 seropositive persons without HIV infection, oral TDF/FTC and intravaginal tenofovir are ineffective at reducing the risk for HSV-2 shedding or recurrences (477).
Acyclovir 400 mg orally 2 times/day
Valacyclovir 500 mg orally once a day*
Valacyclovir 1 gm orally once a day
Famciclovir 250 mg orally 2 times/day
* Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens for persons who have frequent recurrences (i.e., ≥10 episodes/year).
Famciclovir appears somewhat less effective for suppression of viral shedding (478). Ease of administration and cost also are key considerations for prolonged treatment.
Recurrent HSV-1 Genital Herpes
Recurrences are less frequent after the first episode of HSV-1 genital herpes, compared with genital HSV-2 genital herpes, and genital shedding rapidly decreases during the first year of infection (479). No data are available regarding the efficacy of suppressive therapy for preventing transmission among persons with HSV-1 genital herpes infection. Because of the decreased risk for recurrences and shedding, suppressive therapy for HSV-1 genital herpes should be reserved for those with frequent recurrences through shared clinical decision-making between the patient and the provider.
Episodic Therapy for Recurrent HSV-2 Genital Herpes
Episodic treatment of recurrent herpes is most effective if therapy is initiated 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. Acyclovir, famciclovir, and valacyclovir appear equally effective for episodic treatment of genital herpes (466–470).
Acyclovir 800 mg orally 2 times/day for 5 days
Acyclovir 800 mg orally 3 times/day for 2 days
Famciclovir 1 gm orally 2 times/day for 1 day
Famciclovir 500 mg once, followed by 250 mg 2 times/day for 2 days
Famciclovir 125 mg 2 times/day for 5 days
Valacyclovir 500 mg orally 2 times/day for 3 days
Valacyclovir 1 gm orally once daily for 5 days
*Acyclovir 400 mg orally 3 times/day is also effective, but are not recommended because of frequency of dosing.
Intravenous (IV) acyclovir therapy (5–10 mg/kg body weight IV every 8 hours) 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). HSV-2 meningitis is a rare complication of HSV-2 genital herpes infection that affects women more than men (480). IV therapy should be considered until clinical improvement followed by oral antiviral therapy to complete >10 days of total therapy. Longer duration is recommended for CNS complications. HSV-2 meningitis is characterized clinically by signs of headache, photophobia, fever, meningismus, and cerebrospinal fluid (CSF) lymphocytic pleocytosis, accompanied by mildly elevated protein and normal glucose (481). Optimal therapies for HSV-2 meningitis have not been well studied (482); however, acyclovir 5–10 mg/kg body weight IV every 8 hours until clinical improvement is observed, followed by high-dose oral antiviral therapy (valacyclovir 1 g 3 times/day) to complete a 10- to 14-day course of total therapy, is recommended. For patients with previous episodes of documented HSV-2 meningitis, oral valacyclovir may be used for the entire course during episodes of recurrent HSV-2 meningitis. A randomized clinical trial indicated that suppressive therapy (valacyclovir 500 mg 2 times/day) did not prevent recurrent HSV-2 meningitis episodes; however, the dose might not have been sufficient for CNS penetration (483). Valacyclovir 500 mg 2 times/day is not recommended for suppression of HSV-2 meningitis; higher doses have not been studied in clinical trials. HSV meningitis should be distinguished from encephalitis, which requires a longer course (14–21 days) of IV therapy. Impaired renal function warrants an adjustment in acyclovir dosage.
Hepatitis is a rare manifestation of disseminated HSV infection, often reported among pregnant women who acquire HSV during pregnancy (484). Pregnant women in any trimester can present with fever and hepatitis (markedly elevated transaminases) but might not have any genital or skin lesions. HSV hepatitis is associated with fulminant liver failure and high mortality (25%). Therefore, a high index of suspicion for HSV is necessary, with a confirmatory diagnosis by HSV PCR from blood (485). Among pregnant women with fever and unexplained severe hepatitis, disseminated HSV infection should be considered, and empiric IV acyclovir should be initiated pending confirmation (484).
Consistent and correct condom use has been reported in multiple studies to decrease, but not eliminate, the risk for HSV-2 transmission from men to women (486–488). Condoms are less effective for preventing transmission from women to men (489). Two randomized clinical trials of medical male circumcision (MMC) demonstrated a decreased risk for HSV-2 acquisition among men in Uganda and South Africa (66,68). Results from a third trial conducted in Kenya did not demonstrate a substantial difference in HSV-2 acquisition among men who received MMC (490). A systematic review indicated high consistency for decreased risk for HSV-2 acquisition among women with a male partner who underwent MMC (491). These data indicate that MMC can be associated with decreased risk for HSV-2 acquisition among adult heterosexual men and with decreased risk for HSV-2 transmission from male to female partners.
Randomized clinical trials have demonstrated that PrEP with daily oral TDF/FTC decreases the risk for HSV-2 acquisition by 30% in heterosexual partnerships (492). Pericoital intravaginal tenofovir 1% gel also decreases the risk for HSV-2 acquisition among heterosexual women (493). Among MSM and transgender women, daily oral TDF/FTC decreases the risk for severe ulcers with symptomatic genital HSV-2 infection but not for HSV-2 acquisition (494). Insufficient evidence exists that TDF/FTC use among those who are not at risk for HIV acquisition will prevent HSV-2 infection, and it should not be used for that sole purpose. Oral TDF does not prevent HSV-2 acquisition among persons with HIV infection who are taking TDF as part of their ART regimen (495). No data indicate that antivirals (acyclovir, valacyclovir, or famciclovir) can be taken as PrEP by persons without HSV-2 to prevent its acquisition.
Counseling of persons with genital herpes and their sex partners is crucial for management. The goals of counseling include helping patients cope with the infection and preventing sexual and perinatal transmission. Although initial counseling can be provided at the first visit, patients often benefit from learning about the chronic aspects of the disease after the acute illness subsides. Multiple resources, including Internet sites and printed materials, are available to assist patients, their partners, and clinicians who provide counseling (496,497) (https://www.ashasexualhealth.org and https://www.cdc.gov/std/herpes).
Although the psychological effect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecognized genital herpes appears minimal and transient (498,499), certain persons with HSV infection might express anxiety concerning genital herpes that does not reflect the actual clinical severity of their disease; the psychological effect of HSV infection can be substantial. Common concerns about genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children.
When counseling persons with symptomatic HSV-2 genital herpes infection, the provider should discuss the following:
- The natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and the attendant risks for sexual transmission of HSV to occur during asymptomatic periods (asymptomatic viral shedding is most frequent during the first 12 months after acquiring HSV-2).
- The effectiveness of daily suppressive antiviral therapy for preventing symptomatic recurrent episodes of genital herpes for persons experiencing a first episode or recurrent genital herpes.
- The effectiveness of daily use of valacyclovir in reducing risk for transmission of HSV-2 among persons without HIV (473) and use of episodic therapy to shorten the duration of recurrent episodes.
- The importance of informing current sex partners about genital herpes and informing future partners before initiating a sexual relationship.
- The importance of abstaining from sexual activity with uninfected partners when lesions or prodromal symptoms are present.
- The effectiveness of male latex condoms, which when used consistently and correctly can reduce, but not eliminate, the risk for genital herpes transmission (486–488).
- The type-specific serologic testing of partners of persons with symptomatic HSV-2 genital herpes to determine whether such partners are already HSV seropositive or whether risk for acquiring HSV exists.
- The low risk for neonatal HSV except when genital herpes is acquired late in pregnancy or if prodrome or lesions are present at delivery.
- The increased risk for HIV acquisition among HSV-2 seropositive persons who are exposed to HIV (76,471).
- The lack of effectiveness of episodic or suppressive therapy among persons with HIV infection to reduce risk for transmission to partners who might be at risk for HSV-2 acquisition.
When counseling persons with asymptomatic HSV-2 genital herpes infection, the provider should consider the following:
- Asymptomatic persons who receive a diagnosis of HSV-2 by type-specific serologic testing (with confirmatory testing, if needed) should receive education about the symptoms of genital herpes infection (see Diagnostic Considerations).
- Episodic and suppressive antiviral therapies are used predominantly to treat recurrences, prevent recurrences, and prevent transmission to sex partners of persons with symptomatic HSV-2 infection.
- For patients with serological evidence of HSV-2 (with combination testing if needed) without symptomatic recurrences, neither episodic nor suppressive therapy is indicated for prevention of recurrences (see Diagnostic Considerations).
- Among persons with asymptomatic infection, the efficacy of suppressive therapy to prevent HSV-2 transmission to sex partners has not been studied.
- Because of the decreased risk for shedding among those with asymptomatic HSV-2 genital herpes, the benefit of suppressive therapy for preventing transmission is unknown among this population.
When counseling persons with HSV-1 genital herpes infection, the provider should consider the following:
- Persons with virologic laboratory-documented symptomatic HSV-1 genital herpes infection should be educated that the risk for recurrent genital herpes and genital shedding is lower with HSV-1 infection, compared with HSV-2 infection.
- Because of the decreased risk for recurrences and shedding, suppressive therapy for HSV-1 genital herpes should be reserved for those with frequent recurrences.
- For patients with frequently recurring HSV-1 genital herpes, suppressive therapy might be considered. Suppressive therapy to prevent HSV-1 transmission to sex partners has not been studied.
For persons with symptomatic HSV-1 genital herpes or asymptomatic HSV-2 genital herpes, suppressive therapy can be considered for those who have substantial psychosocial distress caused by the diagnosis of genital herpes. For women who have genital herpes, the providers who care for them during pregnancy and those who will care for their newborn infant should be informed of their infection (see Genital Herpes During Pregnancy).
Management of Sex Partners
The sex partners of persons who have symptomatic genital herpes can benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated in the same manner as patients who have symptomatic genital herpes. Asymptomatic sex partners of patients who have symptomatic genital herpes should be asked about a history of genital symptoms and offered type-specific serologic testing for HSV-2. For partners without genital herpes, no data are available on which to base a recommendation for PEP or PrEP with antiviral medications or that they would prevent acquisition, and this should not be offered to patients as a prevention strategy.
Drug Allergy, Intolerance, or Adverse Reactions
Allergic and other adverse reactions to oral acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described (500).
Immunocompromised patients can have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among persons with HIV infection and might be severe, painful, and atypical (501). HSV shedding is increased among persons with HIV infection (502). Whereas ART reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs (503,504). Clinical manifestations of genital herpes might worsen during immune reconstitution early after initiation of ART. HSV-2 type-specific serologic testing can be considered for persons with HIV infection during their initial evaluation, particularly among those with a history of genital symptoms indicative of HSV infection.
Recommended therapy for first-episode genital herpes is the same as for persons without HIV infection, although treatment courses might need to be extended for lesion resolution. Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV infection among persons with HIV (503,504). The risk for GUD increases during the first 6 months after starting ART, especially among persons who have a CD4+ T-cell count <200 cell/mm3. Suppressive antiviral therapy reduces the risk for GUD among this population and can be continued for 6 months after ART initiation (504) when the risk for GUD returns to baseline levels. Suppressive antiviral therapy among persons with HIV and HSV infection does not reduce the risk for either HIV transmission or HSV-2 transmission to susceptible sex partners (88,505). Suppressive antiviral therapy does not delay HIV disease progression and is not associated with decreased risk for HIV-related inflammation among persons taking ART (506). For severe HSV disease, initiating therapy with acyclovir 5–10 mg/kg IV every 8 hours might be necessary.
Acyclovir 400–800 mg orally 2-3 times/day
Famciclovir 500 mg orally 2 times/day
Valacyclovir 500 mg orally 2 times/day
Acyclovir 400 mg orally 3 times/day for 5–10 days
Famciclovir 500 mg orally 2 times/day for 5–10 days
Valacyclovir 1 gm orally 2 times/day for 5–10 days
Acyclovir 400 mg orally 3 times/day
Valacyclovir 500 mg orally 2 times/day
* Treatment recommended starting at 36 weeks’ gestation.
Newborn infants exposed to HSV during birth, as documented by virologic testing of maternal lesions at delivery or presumed by observation of maternal lesions, should be followed clinically in consultation with a pediatric infectious disease specialist. Detailed guidance is available regarding management of neonates who are delivered vaginally in the presence of maternal genital herpes lesions and is beyond the scope of these guidelines; more information is available from the AAP (https://redbook.solutions.aap.org). Surveillance cultures or PCR of mucosal surfaces of the neonate to detect HSV infection might be considered before the development of clinical signs of neonatal herpes to guide treatment initiation. In addition, administration of acyclovir might be considered for neonates born to women who acquired HSV near term because the risk for neonatal herpes is high for these newborn infants. All newborn infants who have neonatal herpes should be promptly evaluated and treated with systemic acyclovir. The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg body weight IV every 8 hours for 14 days if disease is limited to the skin and mucous membranes, or for 21 days for disseminated disease and disease involving the CNS.