Genital HSV Infections
Genital herpes is a chronic, life-long 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 approximately 50 million persons in the United States are infected with this type of genital herpes (318). However, an increasing proportion of anogenital herpetic infections have been attributed to HSV-1 infection, which is especially prominent among young women and MSM (319-321).
Most persons infected with HSV-2 have not had the condition diagnosed. Many such persons have mild or unrecognized infections but shed virus intermittently in the anogenital area. As a result, 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 disease rather than focusing solely on treatment of acute episodes of genital lesions.
The clinical diagnosis of genital herpes can be difficult, because the painful multiple vesicular or ulcerative lesions typically associated with HSV are absent in many infected persons. Recurrences and subclinical shedding are much more frequent for genital HSV-2 infection than for genital HSV-1 infection (322,323). A patient’s prognosis and the type of counseling needed depend on the type of genital herpes (HSV-1 or HSV-2) causing the infection; therefore, the clinical diagnosis of genital herpes should be confirmed by type-specific laboratory testing (321,324). 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 STDs. Persons with genital herpes should be tested for HIV infection.
Cell culture and PCR are the preferred HSV tests for persons who seek medical treatment for genital ulcers or other mucocutaneous lesions. The sensitivity of viral culture is low, especially for recurrent lesions, and declines rapidly as lesions begin to heal. Nucleic acid amplification methods, including PCR assays for HSV DNA, are more sensitive and are increasingly available (325-327). PCR is the test of choice for diagnosing HSV infections affecting the central nervous system and systemic infections (e.g., meningitis, encephalitis, and neonatal herpes). Viral culture isolates and PCR amplicons should be typed to determine which type of HSV is causing the infection. Failure to detect HSV by culture or PCR, especially in the absence of active lesions, does not indicate an absence of HSV infection because viral shedding is intermittent. 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 (IF) assay using fluorescein-labeled monoclonal antibodies is also available to detect HSV antigen from genital specimens, this assay lacks sensitivity (328).
Both type-specific and type-common antibodies to HSV develop during the first several weeks after infection and persist indefinitely. Accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1). Providers should only request type-specific glycoprotein G (gG)-based serologic assays when serology is performed for their patients (329-331).
Both laboratory-based assays and point-of-care tests that provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit are available. The sensitivities of these glycoprotein G type-specific tests for the detection of HSV-2 antibody vary from 80%–98%; false-negative results might be more frequent at early stages of infection (330,332,333). The most commonly used test, HerpeSelect HSV-2 Elisa might be falsely positive at low index values (1.1–3.5) (334-336). Such low values should be confirmed with another test, such as Biokit or the Western blot (337). The HerpeSelect HSV-2 Immunoblot should not be used for confirmation, because it uses the same antigen as the HSV-2 Elisa. Repeat testing is indicated if recent acquisition of genital herpes is suspected. The HerpeSelect HSV-1 Elisa is insensitive for detection of HSV-1 antibody. 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 (337).
Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection. In this instance, education and counseling appropriate for persons with genital HSV infections should be provided. The presence of HSV-1 antibody alone is more difficult to interpret. Many persons with HSV-1 antibody have oral HSV infection acquired during childhood, which might be asymptomatic. However, acquisition of genital HSV-1 is increasing, and genital HSV-1 also can be asymptomatic (318-321,338). 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.
Type-specific HSV serologic assays might be useful in the following scenarios: 1) recurrent genital symptoms or atypical symptoms with negative HSV PCR or culture; 2) clinical diagnosis of genital herpes without laboratory confirmation; and 3) a patient whose partner has genital herpes. HSV serologic testing should be considered for persons presenting for an STD evaluation (especially for those persons with multiple sex partners), persons with HIV infection, and MSM at increased risk for HIV acquisition. Screening for HSV-1 and HSV-2 in the general population is not indicated.
Antiviral chemotherapy offers clinical benefits to most symptomatic patients and is the mainstay of management. Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is 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 antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir (339-347). Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration. Famciclovir also has high oral bioavailability. Topical therapy with antiviral drugs offers minimal clinical benefit and is discouraged.
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 develop severe or prolonged symptoms. Therefore, all patients with first episodes of genital herpes should receive antiviral therapy.
- Acyclovir 400 mg orally three times a day for 7–10 days
- Acyclovir 200 mg orally five times a day for 7–10 days
- Valacyclovir 1 g orally twice a day for 7–10 days
- Famciclovir 250 mg orally three times a day for 7–10 days
*Treatment can be extended if healing is incomplete after 10 days of therapy.
Almost all persons 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 as suppressive therapy to reduce the frequency of recurrences or episodically to ameliorate or shorten the duration of lesions. Some 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 genital HSV-2 transmission to susceptible partners (348,349).
Suppressive Therapy for Recurrent Genital Herpes
Suppressive therapy reduces the frequency of genital herpes recurrences by 70%–80% in patients who have frequent recurrences (345-348); many persons receiving such therapy report having experienced 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 (350,351). Quality of life is improved in many patients with frequent recurrences who receive suppressive therapy rather than episodic treatment (352).
The frequency of genital herpes recurrences diminishes over time in many persons, potentially resulting in psychological adjustment to the disease. Therefore, periodically during suppressive treatment (e.g., once a year), providers should discuss the need to continue therapy. However, neither treatment discontinuation nor laboratory monitoring in a healthy person is necessary.
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 (349). 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 also is likely to reduce 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.
- Acyclovir 400 mg orally twice a day
- Valacyclovir 500 mg orally once a day*
- Valacyclovir 1 g orally once a day
- Famiciclovir 250 mg orally twice a day
*Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens in persons who have very frequent recurrences (i.e., ≥10 episodes per year).
Acyclovir, famciclovir, and valacyclovir appear equally effective for episodic treatment of genital herpes (342-346), but famciclovir appears somewhat less effective for suppression of viral shedding (353). 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.
- Acyclovir 400 mg orally three times a day for 5 days
- Acyclovir 800 mg orally twice a day for 5 days
- Acyclovir 800 mg orally three times a day for 2 days
- Valacyclovir 500 mg orally twice a day for 3 days
- Valacyclovir 1 g orally once a day for 5 days
- Famciclovir 125 mg orally twice daily for 5 days
- Famciclovir 1 gram orally twice daily for 1 day
- Famciclovir 500 mg once, followed by 250 mg twice daily for 2 days
Intravenous (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., meningoencephalitis). The recommended regimen is acyclovir 5–10 mg/kg 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 of total therapy. HSV encephalitis requires 21 days of intravenous therapy. Impaired renal function warrants an adjustment in acyclovir dosage.
Counseling of infected persons and their sex partners is critical to the management of genital herpes. 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, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides. Multiple resources, including websites (http://www.ashasexualhealth.orgExternal) and printed materials, are available to assist patients, their partners, and clinicians who become involved in counseling (354,355).
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 (356,357), some HSV-infected persons 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 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 following topics should be discussed when counseling persons with genital HSV infection:
- the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and the attendant risks of sexual transmission;
- the effectiveness of suppressive therapy for persons experiencing a first episode of genital herpes in preventing symptomatic recurrent episodes;
- use of episodic therapy to shorten the duration of recurrent episodes;
- importance of informing current sex partners about genital herpes and informing future partners before initiating a sexual relationship;
- potential for sexual transmission of HSV to 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);
- importance of abstaining from sexual activity with uninfected partners when lesions or prodromal symptoms are present;
- effectiveness of daily use of valacyclovir in reducing risk for transmission of HSV-2, and the lack of effectiveness of episodic or suppressive therapy in persons with HIV and HSV infection in reducing risk for transmission to partners who might be at risk for HSV-2 acquisition;
- effectiveness of male latex condoms, which when used consistently and correctly can reduce (but not eliminate) the risk for genital herpes transmission (27,358,359);
- HSV infection in the absence of symptoms (type-specific serologic testing of the asymptomatic partners of persons with genital herpes is recommended to determine whether such partners are already HSV seropositive or whether risk for acquiring HSV exists);
- risk for neonatal HSV infection; and
- increased risk for HIV acquisition among HSV-2 seropositive persons who are exposed to HIV (suppressive antiviral therapy does not reduce the increased risk for HIV acquisition associated with HSV-2 infection) (75,347).
Asymptomatic persons who receive a diagnosis of 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 educated about the clinical manifestations of genital herpes.
Pregnant women and women of childbearing age who have genital herpes should inform the providers who care for them during pregnancy and those who will care for their newborn infant about their infection. More detailed counseling messages are described in Special Considerations, Genital Herpes in Pregnancy.
The sex partners of persons who have genital herpes can benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital herpes. Asymptomatic sex partners of patients who have genital herpes should be questioned concerning histories of genital lesions and offered type-specific serologic testing for HSV infection.
Allergy, Intolerance, and Adverse Reactions
Allergic and other adverse reactions to oral acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described (360).
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. HSV shedding is increased in persons with HIV infection. Whereas antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs (361,362). Clinical manifestations of genital herpes might worsen during immune reconstitution early after initiation of antiretroviral therapy.
Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among persons with HIV infection (363-365). HSV type-specific serologic testing can be offered to persons with HIV infection during their initial evaluation if infection status is unknown, and suppressive antiviral therapy can be considered in those who have HSV-2 infection. Suppressive anti-HSV therapy in persons with HIV infection does not reduce the risk for either HIV transmission or HSV-2 transmission to susceptible sex partners (71,366).
Recommended Regimens for Daily Suppressive Therapy in Persons with HIV
- Acyclovir 400–800 mg orally twice to three times a day
- Valacyclovir 500 mg orally twice a day
- Famciclovir 500 mg orally twice a day
Recommended Regimens for Episodic Infection in Persons with HIV
- Acyclovir 400 mg orally three times a day for 5–10 days
- Valacyclovir 1 g orally twice a day for 5–10 days
- Famciclovir 500 mg orally twice a day for 5–10 days
For severe HSV disease, initiating therapy with acyclovir 5–10 mg/kg IV every 8 hours might be necessary.
Antiviral resistant HSV
If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate obtained for sensitivity testing (367). Such persons should be managed in consultation with an infectious-disease specialist, and alternate therapy should be administered. All acyclovir-resistant strains are also resistant to valacyclovir, and most are resistant to famciclovir. Foscarnet (40–80 mg/kg IV every 8 hours until clinical resolution is attained) is often effective for treatment of acyclovir-resistant genital herpes (368,369). Intravenous cidofovir 5 mg/kg once weekly might also be effective. Imiquimod is a topical alternative (370), as is topical cidofovir gel 1%; however, cidofovir must be compounded at a pharmacy (371). These topical preparations should be applied to the lesions once daily for 5 consecutive days.
Clinical management of antiviral resistance remains challenging among persons with HIV infection, necessitating other preventative approaches. However, experience with another group of immunocompromised persons (hematopoietic stem-cell recipients) demonstrated that persons receiving daily suppressive antiviral therapy were less likely to develop acyclovir-resistant HSV compared with those who received episodic therapy for outbreaks (372).
Most mothers of newborns who acquire neonatal herpes lack histories of clinically evident genital herpes (373,374). The risk for transmission to the neonate from an infected mother is high (30%–50%) among women who acquire genital herpes near the time of delivery and low (<1%) among women with prenatal histories of recurrent herpes or who acquire genital HSV during the first half of pregnancy (375,376).
Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the neonate to herpetic lesions and viral shedding during delivery. Because the risk for herpes is highest in newborn infants of women who acquire genital HSV during late pregnancy, these women should be managed in consultation with maternal-fetal medicine and infectious-disease specialists.
Women without known genital herpes should be counseled to abstain from vaginal intercourse during the third trimester with partners known or suspected of having genital herpes. In addition, pregnant women without known orolabial herpes should be advised to abstain from receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes. Type-specific serologic tests may be useful for identifying pregnant women at risk for HSV infection and guiding counseling regarding the risk for acquiring genital herpes during pregnancy. For example, such testing could be offered to women with no history of genital herpes whose sex partner has HSV infection. However, the effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women by infected partners has not been studied. Routine HSV-2 serologic screening of pregnant women is not recommended.
All pregnant women should be asked whether they have a history of genital herpes. At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. Although cesarean delivery does not completely eliminate the risk for HSV transmission to the neonate, women with recurrent genital herpetic lesions at the onset of labor should deliver by cesarean delivery to reduce the risk for neonatal HSV infection.
Many infants are exposed to acyclovir each year, and no adverse effects in the fetus or newborn attributable to the use of this drug during pregnancy have been reported. Acyclovir can be safely used to treat women in all stages of pregnancy, along with those who are breastfeeding (317,377). Although data regarding prenatal exposure to valacyclovir and famciclovir are limited, data from animal trials suggest these drugs also pose a low risk in pregnant women. Acyclovir can be administered orally to pregnant women with first-episode genital herpes or recurrent herpes and should be administered IV to pregnant women with severe HSV infection. Suppressive acyclovir treatment late in pregnancy reduces the frequency of cesarean delivery among women who have recurrent genital herpes by diminishing the frequency of recurrences at term (378-380). However, such treatment may not protect against transmission to neonates in all cases (381). No data support use of antiviral therapy among HSV-seropositive women without a history of genital herpes.
Recommended regimen for suppressive therapy of pregnant women with recurrent genital herpes *
- Acyclovir 400 mg orally three times a day
- Valacyclovir 500 mg orally twice a day
*Treatment recommended starting at 36 weeks of gestation. (Source: American College of Obstetricians and Gynecologists. Clinical management guidelines for obstetrician-gynecologists. Management of herpes in pregnancy. ACOG Practice Bulletin No. 82. Obstet Gynecol 2007;109:1489–98.)
Newborn infants exposed to HSV during birth, as documented by maternal virologic testing of maternal lesions at delivery or presumed by observation of maternal lesions, should be followed carefully in consultation with a pediatric infectious-disease specialist. Guidance is available on management of neonates who are delivered vaginally in the presence of maternal genital HSV lesions (382).
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 initiation of treatment. 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 infants. All 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 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 that involving the central nervous system.