Genital infection caused by herpes simplex virus: causes, symptoms, diagnosis, treatment

Genital herpes is a recurring viral disease that cannot be completely cured. Two serotypes of the herpes simplex virus have been identified. HSV-1 and HSV-2; HSV-2 is the cause of most cases of recurrent genital herpes. According to serologic studies, about 45 million people in the United States are infected with HSV-2.

Most people infected with HSV-2 have no diagnosis of genital herpes; they have mild or asymptomatic disease, but still have the virus in their genital tract from time to time. In some cases, the first clinical episode of genital herpes manifests as a severe illness requiring hospitalization. Most cases are acquired by people who are unaware that they have a genital HSV infection or who have no symptoms at the time of sexual contact.

Antiviral drugs provide partial control of symptoms and signs of herpes recurrences when used to treat the first clinical episode, recurrent episodes, or as daily suppressive therapy. However, these drugs do not eradicate latent virus and do not affect the risk, frequency, or severity of recurrences after treatment is stopped. Randomized trials show that three antiviral drugs provide clinical benefit in genital herpes: acyclovir, valacyclovir, and famciclovir. Valacyclovir is a valine ester of acyclovir with increased absorption after oral administration. Famciclovir, a precursor of penciclovir, also has high bioavailability when administered orally. Topical acyclovir therapy is significantly less effective than oral acyclovir and is not recommended. More aggressive therapy may be required for episodes of HSV infection in HIV-infected patients. In immunocompromised individuals, episodes of the disease may be more prolonged and severe. Several acyclovir dosing regimens, described below, for both initial and recurrent episodes are recommended based on substantial clinical experience, expert opinion, and FDA-approved drug dosages.

First clinical episode of genital herpes

Management of patients with the first clinical episode of genital herpes includes the administration of antiviral drugs and counseling about the characteristics of this infection, the possibilities of sexual and intrauterine transmission, and methods to reduce the risk of such transmission. From 5 to 30% of first episodes of genital herpes are caused by HSV-1, but recurrent course is more typical for infection caused by HSV-2. Therefore, identification of the type of herpes infection has prognostic value and can be useful in counseling the patient about this disease.

Recommended treatment regimens

Acyclovir 400 mg orally 3 times a day for 7-10 days,

Or Acyclovir 200 mg orally 5 times a day for 7-10 days,

Or Famciclovir 250 mg orally 3 times a day for 7-10 days,

Or Valaciclovir 1.0 g orally 2 times a day for 7-10 days.

NOTE: Treatment may be continued if complete healing has not occurred after 10 days of treatment.

Higher doses of acyclovir (400 mg orally 5 times daily) have been used in studies of their effect in the treatment of first episodes of herpetic proctitis and oral infection (stomatitis or pharyngitis). It is not clear whether these types of mucosal infection require higher doses of acyclovir than those used for genital herpes. Valaciclovir and famciclovir are probably also effective in the treatment of acute herpetic proctitis or oral infection, but clinical experience with these drugs is limited.

Because genital herpes is a recurrent and incurable infection, counseling is an important part of patient management. Although counseling can be provided during the initial visit, many patients use knowledge of the chronic aspects of the disease after the acute period of infection has subsided.

Counseling of patients with genital herpes should include the following points:

• Patients with genital herpes should be counseled about the natural history of the disease, emphasizing the potential risks of recurrent episodes, asymptomatic carriage, and sexual transmission.
• Patients should be advised to abstain from sexual intercourse during the onset of herpes lesions or prodromal symptoms and to inform their sexual partners that they are infected with genital herpes. Condom use should be encouraged during all sexual intercourse with a new or uninfected sexual partner.
• Sexual transmission of HSV can occur during the asymptomatic period of the disease, when genital lesions are absent. Asymptomatic carriage of the virus is more common in patients infected with HSV-2 than HSV-1, as well as in patients with a disease duration of less than 12 months. Such patients should be counseled to prevent further spread of the infection.
• The risk of neonatal infection should be explained to all patients, including men. Women of childbearing age with genital herpes should be advised to inform their physicians who will be caring for them during pregnancy of their infection.
• Patients with a first episode of genital herpes should be advised that episodic antiviral therapy for relapses may shorten the duration of herpetic lesions and that suppressive antiviral therapy may improve or prevent recurrent outbreaks.

Recurrence of genital herpes

Most patients with a first episode of genital herpes will have subsequent episodes of genital lesions. Episodic suppressive antiviral therapy may shorten the duration or improve the course of relapses. Because antiviral therapy is highly effective, the choice of treatment regimen should be discussed with all patients.

If treatment is started during the prodromal period or within the first day of the appearance of lesions, it has a marked effect in many patients. If episodic therapy is chosen, the patient should be provided with antiviral drugs or instructions indicating that treatment should be started at the first sign of the prodromal period or genital lesions.

Daily suppressive therapy reduces the frequency of genital herpes recurrences in at least 75% of patients with frequent recurrences (i.e., 6 or more recurrences per year). Safety and efficacy have been demonstrated in patients treated daily with acyclovir for 6 years and with valacyclovir and famciclovir for 1 year. Suppressive therapy has not been associated with the emergence of clinically significant resistance to acyclovir in immunocompetent patients. After 1 year of continuous suppressive therapy, the advisability of interrupting treatment should be discussed with the patient to assess the patient's psychological preparedness to the manifestations of herpes infection and the frequency of recurrences, since it decreases over time in most patients. Given the insufficient experience with the use of famciclovir and valacyclovir, it is not recommended to use these drugs for more than 1 year.

Suppressive therapy with acyclovir reduces but does not prevent asymptomatic viral shedding. Therefore, it is not known to what extent suppressive therapy can prevent HSV transmission.

Recommended treatment regimens for recurrent infection

Acyclovir 400 mg orally 3 times daily for 5 days,

Or Acyclovir 200 mg orally 5 times a day for 5 days,

Or Acyclovir 800 mg orally 2 times a day for 5 days,

Or Famciclovir 125 mg orally 2 times a day for 5 days,

Or Valaciclovir 500 mg orally 2 times daily for 5 days.

Recommended regimens for daily suppressive therapy

Acyclovir 400 mg orally 2 times a day,

Or Famciclovir 250 mg orally 2 times a day,

Or Valaciclovir 250 mg orally once daily,

Or Valaciclovir 500 mg orally once daily,

Or Valaciclovir 1000 mg orally once a day,

The use of valaciclovir at a daily dose of 500 mg compared with its use at other doses was less effective in patients with a very high relapse rate (more than 10 episodes per year). Several comparative studies of valaciclovir and famciclovir versus acyclovir have demonstrated relatively equal clinical efficacy of the newer drugs and acyclovir. However, valaciclovir and famciclovir are more convenient to use, which is especially important in long-term treatment.

Severe course of the disease

The intravenous method of treatment is recommended for patients with severe disease or complications requiring hospitalization (disseminated infection, pneumonia, hepatitis) or with complications from the central nervous system (meningitis, encephalitis).

Recommended scheme

Acyclovir 5-10 mg/kg body weight IV every 8 hours for 5-7 days or until clinical symptoms resolve.

Management of sexual partners

Sexual partners of patients with genital herpes should be evaluated and counseled. Symptomatic sexual partners should be evaluated as any patient with genital lesions and treated appropriately. However, most persons infected with HSV have no history of typical lesions; such patients and their future sexual partners may benefit from evaluation and counseling. Thus, even asymptomatic partners should be asked about their history of typical and atypical genital lesions, advised to self-examine for such lesions in the future, and advised to seek immediate medical attention if such lesions develop.

Most currently available HSV antibody tests do not differentiate between HSV-1 and HSV-2 antibodies and are therefore not currently recommended. Development and implementation of sensitive and type-specific commercial antibody tests may help guide patient management.

Special Notes

Allergies, intolerances and side effects

Allergic or other adverse reactions to acyclovir, valacyclovir, or famciclovir are not common. Desensitization to acyclovir has been described.

HIV infection

Individuals with weakened immune systems may have prolonged episodes of genital or perianal herpes with severe symptoms of the disease.

HSV lesions are quite common in HIV-infected patients and can be severe, painful, and atypical. Intermittent or suppressive therapy with oral antiviral agents is often successful.

The doses of antiviral drugs required in HIV-infected patients have not yet been determined, but clinical experience clearly shows that immunocompromised patients respond well to higher doses of antiviral drugs. Acyclovir 400 mg orally 3-5 times daily is used, as in other immunocompromised patients. Treatment should be continued until clinical manifestations resolve. Famciclovir 500 mg twice daily has been shown to be effective in reducing relapses and subclinical manifestations in HIV-infected individuals. In immunocompromised individuals, valacyclovir 8 g daily has occasionally been associated with a syndrome resembling hemolytic uremic syndrome or thrombotic thrombocytopenic purpura. However, at doses recommended for the treatment of genital herpes, valacyclovir, as well as acyclovir and famciclovir, are safe for immunocompromised patients. In severe cases, intravenous acyclovir at a dose of 5 mg/kg every 8 hours may be required.

If a patient's herpetic lesions persist despite treatment with acyclovir, it should be assumed that the patient's HSV strain is resistant to acyclovir; such patients should be referred for specialist consultation. For severe disease caused by strains known or suspected to be resistant to acyclovir, alternative treatment should be considered. All acyclovir-resistant strains are also resistant to valacyclovir and, in most cases, to famciclovir. For the treatment of acyclovir-resistant genital herpes, foscarnet, 40 mg/kg body weight intravenously every 8 hours until clinical manifestations resolve, is often effective. Application of 1% cidofovir gel to the herpetic lesions is also effective in many patients.

Pregnancy

The safety of systemic acyclovir therapy for genital herpes in pregnant women has not been established. GlaxoWellcome and the CDC continue to monitor selected cases of acyclovir use during pregnancy to evaluate its efficacy and adverse reactions. Women receiving acyclovir or valacyclovir during pregnancy are subject to reporting.

To date, registration data have not revealed an increased risk of serious birth defects or adverse events with acyclovir treatment compared with the general population. These data allow us to reassure women who have received acyclovir during pregnancy that this drug is safe. More data are needed to draw definitive conclusions about the risks of using acyclovir for pregnant women and the fetus. The cases of valacyclovir and famciclovir use are too limited to allow us to draw conclusions about the safety of using these drugs during pregnancy.

If the first episode of genital herpes occurs during pregnancy, oral acyclovir may be used. If the pregnant woman has a serious HSV infection (eg, disseminated infection, encephalitis, pneumonia, or hepatitis), intravenous acyclovir is indicated. Data from studies of acyclovir in pregnant women suggest that acyclovir, when used near term, may reduce the number of cesarean deliveries in women with frequently recurring or newly acquired genital herpes by reducing the incidence of active lesions. However, routine use of acyclovir during pregnancy in women with a history of recurrent genital herpes is not currently recommended.

Perinatal infection

Most mothers whose infants acquire herpes during the neonatal period have no history of clinically evident genital herpes. The risk of transmission to the neonate from an infected mother is high (30-50%) if the woman acquires genital herpes shortly before delivery and is low in women who have had recurrent genital herpes during pregnancy and in women who acquire genital HSV in the first half of pregnancy (~3%). Therefore, to prevent neonatal herpes, it is important to prevent mothers from acquiring HSV during late pregnancy. Pregnant women whose partners have genital or oral herpes should be advised to avoid unprotected genital or oral sex during late pregnancy. Viral cultures during pregnancy do not predict viral shedding during delivery, so routine cultures are not indicated.

All women should be carefully questioned about genital herpes symptoms and examined before labor begins. Women without symptoms or signs of genital herpes (or prodromal signs) can give birth vaginally. Delivery by cesarean section does not completely eliminate the risk of HSV infection in the newborn.

Infants infected with HSV at birth (whether confirmed by isolation of virus in cell culture or by demonstration of herpetic lesions) require close follow-up. Some authorities recommend that such infants should have mucosal cultures to detect HSV infection before clinical symptoms develop. Routine prophylaxis with acyclovir in asymptomatic infants delivered through an infected birth canal is not recommended because the risk of infection in most infants is low. However, infants whose mothers acquired genital herpes during pregnancy are at high risk of neonatal HSV infection and some authorities recommend prophylactic treatment with acyclovir for such infants. Such pregnant women and infants should be managed in consultation with a specialist consultant. All infants with evidence of neonatal herpes should be promptly evaluated and treated with systemic acyclovir. The recommended treatment regimen is acyclovir 30-60 mg/kg/day for 10-21 days.

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