Prevention of genital herpes virus infections

INTRODUCTION — Prevention of genital herpes simplex virus (HSV) infections can avert significant morbidity associated with primary infection and the ongoing discomfort and psychological distress that may occur with recurrences. Preventive measures include patient education, use of barrier protection, and chronic suppressive therapy.

This topic will address measures that are available to prevent HSV transmission. The epidemiology, clinical manifestations, diagnosis, and treatment of HSV infection are discussed elsewhere. (See "Treatment of genital herpes simplex virus infection" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)

COUNSELING AND EDUCATION — Counseling is important for the effective management of the patient with genital HSV, particularly in the setting of a primary or first recognized clinical episode. Many questions invariably arise at the time of diagnosis as to the expected frequency and severity of recurrences and the potential for transmission to others.

Psychological aspects of HSV infection can be distressing for patients, but may be under-appreciated by the clinician. A diagnosis of HSV may evoke anger, disbelief, low self-esteem, and fear of rejection by present and future sexual partners [1]. It is important for the clinician to openly address all of these issues.

Anger is often directed at the current partner and questions regarding partner infidelity may arise at the time of diagnosis. However, the first diagnosed outbreak does not necessarily imply new acquisition [1]. Patients should be counseled that this may be the first recognized outbreak; only serologic testing in concert with virologic testing of the lesions can determine if their current episode represents newly acquired infection.

Recurrence — Patients need to be reassured that recurrences are generally less severe and shorter than the first episode and that episodic treatment of recurrences, or chronic suppression with antiviral therapy, are available therapeutic options. They should be educated about the probability of recurrence, which is much higher with HSV-2 (>90 percent) than HSV-1 infections [2,3]. The natural history of genital HSV is discussed in detail elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Recurrent infection'.)

Reducing risk of transmission — Once a patient is diagnosed with genital HSV infection, counseling should also include prevention of transmission to the partner(s). Patients need to be educated that HSV can be transmitted even when symptoms or genital lesions are absent, due to viral shedding. Direct contact with mucous membranes or skin can lead to viral transmission, even in the absence of sexual intercourse.

Determining partner susceptibility to infection — Prevention of genital herpes can only occur in the context of accurate, laboratory diagnosis. Up to 20 percent of persons clinically diagnosed with genital herpes do not have genital HSV infection [4], and thus remain susceptible when exposed to infected partners. In addition, persons with genital HSV-1 infection remain susceptible to HSV-2 infection, and thus counseling associated with diagnosis of genital HSV-1 infection should include discussion of the potential risk of HSV-2 acquisition.

Sex partners should be included within counseling and education sessions regarding HSV infection [5-7]. Serologic testing should be considered for partners without a clear diagnosis of genital herpes to determine the risk of HSV acquisition. Couples who are serologically discordant should be advised to abstain from intercourse when active lesions or prodromal symptoms are present [8].

The use of barrier methods and antiviral prophylaxis in discordant couples are discussed below. (See 'Condom use' below and 'Chronic suppressive therapy in discordant couples' below.)

Educational resources — Many educational resources are available for patients including the Centers for Disease Control and Prevention (CDC) National Sexually Transmitted Diseases (STD)/HIV Hotline (telephone 1-800-232-4636) where patients can obtain additional counseling and order educational brochures. There is also a nationwide list of HSV support groups available to patients. The Herpes Resource Center (HRC) has an affiliated network of local support (HELP) groups for people concerned about HSV. The groups provide a confidential environment where participants can get information and share concerns with others (www.ashasexualhealth.org).

It is best to give patients written information that they can review at home, because the initial diagnosis can be overwhelming. (See "Patient education: Genital herpes (Beyond the Basics)".)

DISCLOSURE OF HSV STATUS TO SEXUAL PARTNERS — All persons with genital HSV-2 infection should be encouraged to inform their current and future sex partners that they have genital herpes [8].

Retrospective studies evaluating source partners of individuals with newly acquired genital herpes have demonstrated a short interval between initiation of sexual activity and the onset of genital herpes infection.

A clinical study was undertaken to determine whether persons who were aware of their HSV-2 status and disclosed this information to their sexual partners were less likely to transmit HSV-2 infection [9]. Based upon the short incubation period of HSV infection, a time-to-event design was utilized to assess the risk of HSV acquisition among these newly infected patients with the following results:

●Most individuals who acquired genital herpes were in new sexual relationships (median duration 3.5 months).

●The median number of sex acts prior to HSV transmission was 40 (interquartile range, 15-75).

●The median time to HSV-2 acquisition was longer in participants whose partners informed them that they had genital herpes than in those who were not informed (270 days versus 60 days, respectively).

In this study, the risk of HSV-2 transmission was approximately halved when the source partner knew their status and informed their partner. The changes in sexual behavior that accompanied the disclosure, which protected against HSV-2 transmission, were not clear.

Since nearly all infected individuals regularly shed HSV on genital mucosa while remaining asymptomatic, sexual transmission of genital herpes continues [10,11]. The study findings support the use of type-specific serologic assays that can reliably distinguish between HSV-1 and HSV-2 infections to identify individuals with HSV-2 infection [10,12]. Serologic testing coupled with efforts to encourage disclosure of genital herpes infection to sexual partners may provide a pivotal advance in public health strategies adapted to control transmission of genital herpes [10].

AVOIDANCE OF SEXUAL ACTIVITY DURING DISEASE — Sexual activity should be discouraged if lesions or prodromal symptoms (those that precede the appearance of lesions) are present, even if condoms are used. Viral shedding is most likely to occur during these stages. Thus, patients should be encouraged to recognize the symptoms specific to their prodrome (eg, localized genital pain or itching, or neuropathic pain in the buttocks or leg) and avoid exposing susceptible partners to the genital area at that time. While viral shedding may also occur during asymptomatic periods, the frequency of viral shedding is higher during lesional episodes, and the amount of virus present is higher.

CONDOM USE — The use of condoms remains a pivotal strategy for the prevention of genital HSV-2 infection and other sexually transmitted diseases (STDs). Given the potential for subclinical viral shedding, condoms should be used in patients with recurrent genital ulcer disease when lesions are not present, and in patients who only have serologic evidence of HSV-2 (ie, those who have never had symptoms). Individuals with HSV-2 who have prodromal symptoms or active lesions should abstain from sexual activity as described above.

Consistent condom use can decrease the risk of HSV-2 transmission to an uninfected partner by up to 96 percent, and is most effective in preventing transmission from men to women [13-17]. However, patients should be counseled that transmission of HSV-2 still remains a possibility even with consistent condom use due to shedding of virus from mucosa not shielded by condoms, or HSV-1 by unprotected oral-genital contact.

Studies illustrating the efficacy of condoms in reducing HSV-2 transmission include:

●In one analysis of 528 monogamous couples with discordant HSV-2 serostatus (261 susceptible men and 267 susceptible women), condom use during more than 25 percent of sex acts was associated with a lower likelihood of HSV-2 acquisition in susceptible women (adjusted hazard ratio [HR] 0.085) but not in men [14].

●In a second study of 1843 participants, 118 (6 percent) became infected with HSV-2 [15]. Men and women reporting more frequent use of condoms (>75 percent of sex acts) were at lower risk for acquisition of HSV-2 than those who used condoms less frequently (HR 0.74; 95% CI 0.59-0.95).

●In a randomized trial of 911 HIV-1 and HSV-2 discordant couples, condoms were found to reduce the risk of HSV-2 transmission independent of acyclovir therapy, especially from men to women [16]. Using data from an HIV-1 prevention trial, the estimated efficacy of condoms in reducing HSV-2 from men to women was 96 percent (28.5 transmissions per 1000 unprotected sex acts versus 1.3 per 1000 protected sex acts; 95% CI 84-99). There was also a nonsignificant reduction in HSV-2 transmission from women to men (1.7 transmissions per 1000 unprotected sex acts versus 0.6 per 1000 protected sex acts; 95% CI 5-88).

Despite the benefits of using condoms, consistent condom use is difficult in monogamous HSV-2 serodiscordant couples. A study of condom use patterns among 1193 such couples demonstrated that the majority of persons either abstained from sexual activity or used condoms "always" during symptomatic periods; in contrast, condom use was low during asymptomatic periods [18]. Thus, chronic suppressive therapy may further help reduce the risk of HSV transmission.

CHRONIC SUPPRESSIVE THERAPY IN DISCORDANT COUPLES — Chronic daily therapy may be considered for patients who have significant symptoms related to HSV-2 disease. This topic is discussed in detail elsewhere. (See "Treatment of genital herpes simplex virus infection".)

Another reason to consider suppressive therapy for HSV recurrences is to reduce the risk of transmission to the uninfected partner, as discussed below.

Effect on transmission — Valacyclovir (500 mg once daily) can be used to help prevent transmission of HSV-2 to an uninfected sexual partner. This was demonstrated in a large randomized placebo-controlled trial of 1484 immunocompetent, heterosexual, discordant couples [19]. Symptomatic patients with HSV-2 infection received either 500 mg of valacyclovir once daily or placebo. Suppressive therapy led to a significant reduction in overall acquisition of genital HSV-2 infection in the uninfected partner (1.9 versus 3.6 percent, hazard ratio [HR] 0.52; 95% CI 0.27-0.99). Valacyclovir use was also associated with fewer days of viral shedding (2.9 versus 10.8 percent of days) and fewer recurrences of genital herpes (0.11 versus 0.40 per month) in the infected source partner. Therapy was extremely well tolerated over the eight-month study period.

There is some evidence that prophylactic therapy may not be effective in preventing HSV-2 transmission from a subset of immunocompromised hosts to their serodiscordant partners. This was demonstrated in a study of 911 HIV-1 and HSV-2 serodiscordant couples who were randomly assigned to receive acyclovir 400 mg twice daily versus placebo [20]. The median baseline CD4 cell count and HIV-1 plasma RNA load were 470 cells/microL and 3.9 log10 copies/mL, respectively. At study entry, none of the participants were receiving antiretroviral therapy (ART) for their HIV, which was consistent with guidelines at that time. HSV-2 seroconversion occurred in 40 couples receiving acyclovir and 28 couples receiving placebo (HR 1.35; 95% CI 0.83-2.20). It is not known whether daily suppressive therapy will result in a reduced risk of HSV-2 transmission from HIV-infected persons who are receiving ART or from persons who are immunocompromised for reasons other than HIV.

Clinical decision making — We suggest administering suppressive antiviral agents to most HSV-2-infected patients to reduce the risk of transmission to their uninfected partners. This decision is based, in part, upon the immune status of the host patient. Conversations with all patients should emphasize the importance of condom use to decrease HSV-2 transmission to uninfected partners since antiviral therapy reduces, but does not eliminate, viral shedding [21].

Immunocompetent patients — In immunocompetent patients with HSV-2 (including those who are asymptomatic), we administer suppressive antiviral therapy to decrease the risk of HSV-2 transmission to patients who have an at-risk partner. The potential benefits include decreasing symptomatic disease and reducing the chance that an uninfected partner will acquire HSV-2 by approximately 50 percent. The use of suppressive therapy to prevent transmission has not been studied in asymptomatic individuals; however, antiviral treatment is likely to reduce the risk of HSV-2 transmission to the sexual partners of these persons, as viral shedding occurs also in the absence of symptoms. The risks of treatment include mild and infrequent side effects (eg, headaches) and the inconvenience of taking a daily medication.

Immunocompromised patients — We administer suppressive antiviral therapy to immunocompromised individuals to reduce clinical disease. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV", section on 'Treatment strategies for recurrent disease' and "Treatment of genital herpes simplex virus type 2 in people living with HIV", section on 'Immune reconstitution syndrome' and "Treatment of genital herpes simplex virus infection".)

In such patients, suppressive therapy for genital herpes may decrease the risk of transmission to an uninfected partner. However, in certain populations (eg, HIV-infected individuals not on ART) this therapy is unlikely to be effective [20]. Further studies are needed to adequately evaluate the efficacy of antiviral therapy in preventing HSV transmission from an immunocompromised host to an uninfected partner.

Choice of agent — We use valacyclovir or acyclovir for suppressive therapy to prevent HSV-2 transmission in immunocompetent and most immunocompromised patients. Although valacyclovir is the only agent that has been shown to prevent HSV transmission, acyclovir should provide similar benefits since both agents decrease viral shedding comparably [22]. This is important as acyclovir may be a more affordable option. We prefer either of these agents, over famciclovir, since valacyclovir was shown to be better than famciclovir for suppression of clinical disease and viral shedding [23].

Identification of HSV serostatus — The sex partner of an HSV-seropositive patient should be counseled that he or she may have been infected in the past, even if he or she has had no history of genital herpes. Type-specific serologic testing of the asymptomatic partner is recommended when chronic suppressive therapy for HSV is being considered for the sole purpose of avoiding HSV transmission [8].

Duration of therapy — Suppressive acyclovir has been given to patients for up to eight years without adverse effects. Data for valacyclovir and famciclovir are available for up to one year, and these drugs are also well tolerated.

Laboratory monitoring — Laboratory monitoring for toxicity is not required in otherwise healthy persons, even with prolonged administration.

Treatment interruptions — Treatment interruptions to assess the need for continued therapy are not necessary, if the drug is administered for protection of the partner. However, annual discussions of whether the patient wants to continue suppressive therapy are desirable, as the frequency of recurrences decreases over time in many patients. Furthermore, many patients also adjust psychologically to having a diagnosis of genital herpes.

STD SCREENING — Patients with genital herpes are at risk for and should be screened for other sexually transmitted diseases (STDs). Educational efforts should also be made to decrease risky sexual behaviors at the time of diagnosis of genital herpes [24]. (See "Screening for sexually transmitted infections".)

CIRCUMCISION STATUS — Circumcision has been associated with a reduced risk of acquisition of some infectious agents, such as HIV. While a meta-analysis of 26 studies showed no clear effect on HSV-2 infection, a clinical trial of circumcision in Uganda (that was aimed at decreasing HIV transmission) showed a 28 percent reduction in HSV-2 incidence among study participants in the circumcision arm [25,26]. (See "Prevention of sexually transmitted infections".)

INVESTIGATIONAL APPROACHES — Various oral and topical agents are being evaluated for the prevention of HSV-2 acquisition and shedding [27]. As an example, oral tenofovir disoproxil fumarate, when administered for HIV pre-exposure prophylaxis (PrEP), may also reduce the risk of acquiring HSV-2 in certain patients. (See "HIV pre-exposure prophylaxis".)

In women, the effect of vaginally administered tenofovir gel on HSV-2 acquisition was evaluated in 422 HSV-2-negative women from South Africa who participated in a clinical trial designed to assess the efficacy of tenofovir gel in reducing HIV acquisition [28]. The incidence of HSV-2 infection was significantly decreased in the group that received tenofovir gel compared with placebo (10 versus 21 cases per 100 person-years, incidence rate ratio 0.49; 95% CI 0.30-0.77).

However, the role of tenofovir gel in decreasing viral shedding among women with HSV-2 infection is less clear. In a randomized study of 64 immunocompetent women with symptomatic HSV-2 infection, tenofovir vaginal gel did not significantly reduce viral shedding or the number of days with genital lesions [29].

Additional studies are needed before these agents can be recommended for the purpose of HSV-2 prevention in routine care.

VACCINE DEVELOPMENT — Research has focused on the development of preventive and/or therapeutic vaccines for HSV infection [30,31]. However, vaccine development against HSV has not been as successful as efforts against another alpha-herpesvirus, varicella-zoster virus [32]. The correlate of protective immunity against HSV remains unknown, which is a major obstacle to HSV vaccine development [33]. Summaries of some of the major trials of HSV vaccines are listed below.

Immunogenicity and protective efficacy — To date, there is no available HSV vaccine that protects against infection with either HSV-1 or HSV-2 [34]. Several efficacy and immunogenicity trials of HSV-2 vaccines have been performed in humans, with varying outcomes. As examples:

●Two randomized, placebo-controlled trials of a vaccine containing two HSV-2 glycoproteins (gB2 and gD2) were performed in HSV-2-seronegative sexual partners of HSV-2-seropositive individuals and patients seen at sexually transmitted disease (STD) clinics [35]. A total of 2012 vaccine recipients and 1135 placebo subjects were enrolled in the two trials combined. The rates of HSV-2 acquisition were the same in the vaccination and placebo recipients (ie, 4.2 and 4.6 per 100 patient-years, respectively).

●A similar HSV-2 glycoprotein D-subunit recombinant vaccine was evaluated in subjects whose regular partners had a history of genital herpes [36]. There was no overall benefit from vaccination. However, a subset analysis demonstrated significant vaccine efficacy (ie, 74 percent) only among those women who were seronegative for HSV-1 and HSV-2 at baseline.

In light of these results, another large trial was designed to evaluate the efficacy of an HSV-2 glycoprotein D vaccine compared with a placebo vaccine (ie, hepatitis A vaccine) among 8323 women who were seronegative for HSV-1 and HSV-2 infection [34]. Overall, the HSV vaccine was not efficacious in preventing HSV-related infection or disease over the 20 months of follow-up. The vaccine did show modest efficacy against HSV-1 infection (35 percent; 95% CI 13-52) and HSV-1 associated genital disease (58 percent; 95% CI 12-80). Although the vaccine was immunogenic at month 7 after completion of the vaccine, neutralizing antibodies were undetectable by study month 16. In a subsequent study, protection against HSV-1 infection appeared to be associated with neutralizing antibodies directed against the virus [37].

The reasons for the disparate efficacy outcomes in the various trials are not clear, and a safe and effective HSV vaccine is not on the immediate horizon.

Therapeutic vaccine — Several therapeutic vaccine trials have been conducted to "boost" natural immunity in persons with prior HSV-2 infection in an effort to decrease recurrences [38-41].

A trial of gD2/alum vaccine showed that immunization of HSV-2 seropositive persons with a history of genital herpes reduced the number of recurrences (0.42 per month in vaccines versus 0.55 in placebo recipients) [38]. However, two other studies (one of a similar vaccine and another using a replication-defective HSV vaccine) did not demonstrate any clinical benefit [39,40].

Several therapeutic HSV-2 vaccine trials are underway at this time, and two vaccines have shown partial efficacy in reducing viral shedding following immunization [42]. Studies of other therapeutic vaccine constructs are ongoing [43].

PREGNANCY — During pregnancy, the major concern regarding HSV infection relates to the morbidity and mortality associated with neonatal infection. Vertical transmission usually results from infant exposure to HSV in the birth canal at delivery, most often in a woman with a subclinical newly acquired genital HSV infection. The prevention of HSV infection in the pregnant woman is discussed elsewhere. (See "Genital herpes simplex virus infection and pregnancy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)

SUMMARY AND RECOMMENDATIONS

●Prevention of genital herpes simplex virus type 2 (HSV-2) infections can avert significant morbidity associated with primary infection and the ongoing discomfort and psychological distress that may occur with recurrences. (See 'Introduction' above.)

●Counseling at the time of diagnosis of HSV infection is important to educate the patient regarding the high probability of recurrence and the prevention of transmission to sexual partner(s). The diagnosis of genital HSV infection can be associated with significant psychological stress. (See 'Counseling and education' above.)

●Patients should be counseled that viral shedding, which can occur during asymptomatic periods, can lead to transmission. (See 'Disclosure of HSV status to sexual partners' above.)

●Consistent condom use has been associated with a decline in transmission of genital HSV infection, especially from men to women. (See 'Condom use' above.)

●For most patients with genital HSV-2 infection and an uninfected partner, we administer chronic suppressive therapy to reduce clinical recurrences and viral transmission. Valacyclovir (500 mg daily) is the best-studied regimen for this specific indication and offers the convenience of once-daily dosing. However, acyclovir may be a reasonable and more affordable alternative. (See 'Chronic suppressive therapy in discordant couples' above.)

●Patients with genital herpes are at risk for other sexually transmitted diseases (STDs) and should be screened. (See "Prevention of sexually transmitted infections".)

●No effective prophylactic or therapeutic vaccine currently exists, although vaccine development is ongoing. (See 'Vaccine development' above.)