Genital Herpes

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SECTION 2 Syndromes by Body System: Sexually Transmitted Diseases

Genital Herpes CHRISTINE JOHNSTON  |  ANNA WALD

KEY CONCEPTS • Genital herpes is caused by either herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) and is the leading cause of genital ulcer disease worldwide. • HSV-1 and HSV-2 cause lifelong infection by establishing a latent reservoir in the sacral ganglion. Infection is characterized by a wide spectrum of disease, with most people having mild or subclinical infection. • Sexual transmission may occur during periods of symptomatic or subclinical genital shedding. • The diagnostic tests of choice are type-specific serologic assays that distinguish between antibody to HSV-1 and HSV-2 and polymerase chain reaction assays to detect HSV from genital ulcers. • Transmission may be prevented through use of condoms, disclosure of genital herpes to sexual partners, use of daily suppressive antiviral therapy, and avoidance of sexual activity when genital symptoms or lesions are present. • Genital herpes recurrences may be managed with use of antiviral agents, either daily suppressive therapy to prevent recurrences and transmission to sexual partners or with short courses of episodic treatment to decrease the duration of recurrences.

Epidemiology Herpes simplex virus type 2 (HSV-2) is the most prevalent sexually transmitted infection worldwide. Genital herpes is caused predominantly by HSV-2; however, herpes simplex virus type 1 (HSV-1) accounts for an increasing proportion of genital herpes infections. As of 2003, the global prevalence of HSV-2 in persons aged 15–49 was estimated at 536 million people.1 The seroprevalence in women is approximately twofold higher than men, and seroprevalence increases with age and number of sexual partners. Worldwide, HSV-2 sero­ prevalence varies widely, with 10–40% of women infected in several European countries, and up to 80% of women in highly endemic settings such as sub-Saharan Africa2 (Figure 62-1). In the USA, the 2007– 2010 NHANES study estimated that 15.5% of adults are HSV-2 seropositive,3 a significant decline from a peak of 21.2% in 1988–1994.4 However, racial disparities in the USA have worsened over that period, with 41.8% seroprevalence among non-Hispanic blacks, compared to 11.3% seroprevalence among non-Hispanic whites.4 Overall, 87.4% of persons who were HSV-2-seropositive had not been told by a healthcare professional that they had HSV-2 infection. Globally, there are estimated to be 23.6 million new infections per year.1 Prospective studies in high-risk populations in the USA, such as in sexually transmitted diseases (STD) clinics, have shown an incidence of 11.7 per 100 person-years.5 In settings with high HSV-2 seroprevalence, rates increase markedly with initiation of sexual activity during adolescence, from 7.3% in 15-year-olds to 33.5% at 24 years of age in women.6 Similar increases are seen in men, from 3.1% at age 15 to 14.4% at age 24,6 with up to 43% of uncircumcised men infected by age 24 in some populations.7 HSV-1 is typically acquired orally during childhood with >80% of the population infected.2 The seroprevalence of HSV-1 in the USA has declined by 7% over the past 15 years, with a particularly dramatic



29% decline in adolescents aged 14–19 over the past 35 years.8 This decline has been associated with the changing epidemiology of genital herpes, with HSV-1 now causing the majority of first-episode genital herpes in women under age 26 and in men who have sex with men. As estimates of genital herpes infection rely on HSV-2 seroprevalence, the true prevalence of genital herpes is underestimated by serologic data. Genital herpes is the leading cause of genital ulcer disease (GUD) worldwide in multiple studies, with HSV DNA present in 40–70% of genital ulcers in patients presenting to STD clinics or for evaluation of GUD.9,10 HSV-2 is highly prevalent among persons infected with human immunodeficiency virus (HIV), with 60% of HIV-infected persons in the USA coinfected with HSV-211 and 80–90% of persons coinfected in Peru and African populations.12,13 HSV-2 infection increases acquisition of HIV infection two- to fourfold in both men and women14,15 and GUD is a risk factor for HIV-1 transmission.16 Approximately half of HIV infections are attributable to HSV-2 in high-prevalence settings.14

Pathogenesis HSV-1 and HSV-2 are enveloped, double-stranded DNA viruses with a genome of ~152 000 base pairs which do not integrate into the host genome and are believed to have diverged 8–10 million years ago.17 The two viruses have ~50% DNA and 80% amino acid homology; the genomes encode for ~77 proteins. HSV-1 and HSV-2 have a DNA core, an icosahedral capsid surrounded by tegument, and a hostderived lipid bilayer envelope with viral glycoproteins, many of which are essential for viral entry and productive infection. The viral particle is 150–200 nm in size (Figure 62-2). HSV-1 and HSV-2 are transmitted through close contact with infected genital secretions. The virus is labile outside of the host, and therefore dies quickly within minutes; transmission through inanimate objects has not been documented. The virus infects epithelial cells at mucosal or skin surfaces through micro-ulcerations, then replicates and infects sensory nerve endings, and undergoes retrograde transportation up nerve axons until it arrives at the sacral ganglion (Figure 62-3). Here, the virus establishes latency, which is characterized by a restricted gene expression program of the ‘latency associated transcript (LAT)’ and viral microRNAs.18 The virus evades the immune response within the sacral ganglion and cannot be eliminated. The ganglion therefore acts as a reservoir for lifelong infection. The virus frequently reactivates, traveling down axons back to the periphery, where it infects epithelial cells and undergoes lytic infection, causing either subclinical shedding or recurrent genital ulcerations. Importantly, HSV-2 reactivates from the sacral ganglion more frequently than HSV-1, likely driven by differences between HSV-1 and HSV-2 LAT, since animal models have shown that exchanging the HSV-2 LAT for HSV-1 LAT results in similar genital reactivation rates as HSV-1.19 While HSV-2 was previously believed to exist in a latent or dormant state between symptomatic recurrences, studies using daily swabs or multiple swabs per day have demonstrated that the virus reactivates frequently, with genital shedding present on 20% of days when measured by HSV polymerase chain reaction (PCR) in people with a history of symptomatic infection, and 10% of days in those with asymptomatic infection.20 While shedding rates decline from a mean of 26% in the first year after primary infection to a mean of 13%, thereafter shedding rates remain relatively stable for up to 9 years post infection, with a slight additional decline to a mean 9% 10 years or

567

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SECTION 2  Syndromes by Body System: Sexually Transmitted Diseases

HSV-2 seroprevalence in women

Prevalence (%) >50 41–50 31–40 21–39 11–29 0–10

Figure 62-1  HSV-2 seroprevalence in women. The map is based on studies performed in general population or antenatal clinics using type-specific HSV serology that can differentiate between HSV-1 and HSV-2. Countries for which no data are available are indicated in white. (Adapted from Schiffer JT, Corey L. Rapid host immune response and viral dynamics in herpes simplex virus-2 infection. Nat Med 2013;19(3):280-90.)

more after infection.21 However, the ranges of possible rates are very broad with few people having very rare reactivation and few persistently shedding virus on 50% of days or more. Most subclinical shedding episodes are short, lasting a median of 13 hours,22 suggesting a rapid host immune response. Mathematical modeling suggests that a small number of virions are released by neurons into the genital tract on a daily basis.23 These precise genital sampling studies have redefined our understanding of HSV-2 genital herpes from an inactive infection with occasional recurrences to an active infection, which induces chronic inflammation in the genital tract. Innate, humoral and cell-mediated immunity are all important for controlling genital herpes infections. Upon initial contact with HSV, toll like receptors (TLRs) are activated, inducing an antiviral state and activating natural killer and plasmacytoid dendritic cells.24 Antibody responses including IgG and IgA which are acquired early after infection may provide some protection against acquisition of, or severity of, genital HSV as neonates are at greatest risk for acquisition when mothers acquire the virus during or close to time of delivery, suggesting that transplacental transfer of antibody mitigates the risk of infection. During HSV recurrences, infiltration of CD8+ T cells is associated with clearance of virus.25 HSV-specific CD8+ T cells are localized at peripheral sensory nerves at skin surfaces for weeks after genital herpes recurrences.26 Recently described tissue resident memory CD8+ T cells located at sites of genital ulcers may be important in containing viral shedding and recurrences.27 CD4+ T cells are also essential for an effective immune response, especially lesion containment, as shown by the severe disease in lymphopenic patients with advanced HIV infection. HSV-1 and HSV-2 have evolved several strategies to evade the host immune response, with several proteins that downregulate major histocompatibility complex (MHC) receptors, prevent activation of interferon signaling28 and downregulate secretory leukocyte protease inhibitor.

TABLE 62-1 

Prevention Strategies for HSV-2

Prevention Strategy

Effect

Limitation

Avoid sex when lesions present

Unknown

Requires recognition of genital herpes recurrence

Condom use

30–50% decreased risk of HSV-2 acquisition with consistent use

Requires use, infected areas may not be covered by condoms

Daily suppressive antiviral therapy

48% decreased risk of HSV–2 transmission

Requires daily use Breakthrough shedding may occur

Disclosure of HSV-2 seropositivity

50% decreased risk of transmission

Requires knowledge of HSV-2 infection

Prevention Prevention of genital herpes transmission requires multiple strategies, since no single strategy is 100% effective (Table 62-1). Patients should be educated that while the greatest risk of transmission may occur during genital prodrome or lesions, when viral shedding is highest,29 transmission may also occur during periods of subclinical shedding, when the virus is present on epithelial surfaces without signs or symptoms of a genital herpes recurrence. Because lesions are relatively infrequent, most HSV-2 transmissions occur during periods of subclinical shedding.30



Chapter 62  Genital Herpes

569

The herpes simplex virion

The core

Surface glycoproteins

The herpes simplex core is linear, doublestranded DNA. The DNA core circularizes with onset of transcription, and the majority of viral synthesis is due to a ‘rolling circle’ mechanism. The genome contains approximately 150 kbp, encoding at least 82 transcribed open reading frames

There are at least 11 different glycosylated protein spikes projecting from the virion envelope, designated gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL, and gM. The surface glycoproteins are thought to be important in virion–cell surface attachment and penetration. However, the function of all of the glycoproteins is not well known

The capsid

The envelope

The capsid consists of 162 capsomers forming an icosadeltahedron, approximately 100 nm in diameter

Herpex simplex viruses have a trilaminar envelope consisting of proteins and lipids derived from altered cellular membranes

The tegument An amorphous layer of variable thickness, the tegument is interspaced between the capsid and the envelope. The tegument layer contains several virion proteins including the virion host shut-off (VHS) protein

Figure 62-2  The herpes simplex virion. This consists of a dsDNA core surrounded by a capsid, an amorphous tegument layer and a lipid envelope with numerous glycoprotein spikes. The overall diameter is 150–200 nm. Virus replication takes place within the nucleus of the infected cell. The envelope is gained as the virion passes through the nuclear membrane. Replication of virus within the host cell results in cell lysis and destruction. Latent virus does not cause neural cell lysis within ganglia.

CONDOM USE Consistent condom use is associated with a 30–50% decreased risk of HSV-2 transmission, which is much lower efficacy as compared with other sexually transmitted infections (STIs).31 This is likely due to mucosal exposure to areas that are either shedding virus or susceptible to infection that are not protected by condoms.

DAILY SUPPRESSIVE ANTIVIRAL THERAPY Suppressive antiviral therapy decreases HSV-2 genital shedding rates by 70–80%.32 A study in HIV-seronegative, HSV-2 discordant couples in which the symptomatic HSV-2 infected partner took valaciclovir 500 mg daily demonstrated a 48% decreased risk of HSV-2 transmission to the susceptible partner, compared with placebo.33 Breakthrough shedding has been shown to occur on both standard and high-dose daily valaciclovir, which is likely responsible for the lack of greater efficacy.34 Suppressive aciclovir for prevention of HSV-2 transmission has not been studied rigorously in clinical trials but is expected to have

similar outcomes based on similar reduction in HSV-2 genital shedding.32 Suppressive therapy for prevention of HSV-2 transmission from HIV/HSV-2 coinfected individuals is not effective.35

DISCLOSURE OF GENITAL HSV-2 INFECTION In a study of 199 patients who acquired HSV-2 infection, patients who had partners who disclosed their HSV-2 status had 50% lower risk of HSV-2 acquisition as compared to those who did not disclose their status.36 Most patients who acquired genital herpes did not believe the transmitting partner was aware that they had genital herpes infection; this mirrors the high rate of unrecognized infection seen in serologic surveys.

PERSONAL KNOWLEDGE OF SEROSTATUS Routine screening for HSV-1 or HSV-2 antibodies is not recommended by the US Preventative Task Force or the US Centers for Disease Control (CDC). Per CDC guidelines, HSV-2 antibody

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SECTION 2  Syndromes by Body System: Sexually Transmitted Diseases

Pathogenesis and transmission of genital HSV infection

Initial infection

Inital infection with retrograde transport of HSV to sensory nerve ganglia

Epidermis

Dermis

Sensory ganglia

Sensory neuron axon

Latency

Transmission

Latency maintaned by immune surveillance; immune control of virus also present at the mucosa

Mucosal viral shedding leads to sexual or perinatal transmission

HSV in latent stage HSV nucleocapsid Enveloped herpes simplex virus

Reactivation

Reactivation from latency with mucosal shedding and lesions; virus travels anterograde to skin or mucosae

Figure 62-3  Pathogenesis and transmission of genital HSV infection. The pathogenesis of initial HSV infection through skin or mucosal surfaces, infection of sensory nerve endings and transport to sensory ganglia, and establishment of persistent infection in ganglia is shown. The virus reactivates to cause genital ulcers or asymptomatic shedding, which can result in transmission to sexual partners and neonates. (From Gupta R, Warren T, Wald A. Genital herpes. The Lancet 2007;370(9605):2127-37.)

screening should be available at STD clinics and can be considered for persons presenting for STD evaluation, those with partners with HSV-2 and those with atypical symptoms that may be compatible with mild recurrent HSV-2 disease.29 Concerns about routine screening include a low positive predictive value in low prevalence settings and false-positive results. In addition, concerns about stigma, anxiety and depression in persons with a positive diagnosis persist, despite data suggesting that there are no long-term psychologic sequelae after being diagnosed with asymptomatic HSV-2 infection.37

careful examination for presence of genital ulcers should be performed. Cesarean section should not be performed in women with genital herpes in the absence of genital lesions. For women with known genital herpes, invasive procedures such as fetal scalp monitoring should be avoided during delivery if possible. Since the risk of transmission to the neonate is greatest in those who acquire genital herpes close to the time of labor, women who have first-episode genital herpes during pregnancy and their infants should be closely followed.

PREVENTION OF GENITAL HSV-1

A vaccine that could protect against HSV-1 and HSV-2 is highly desired by physicians and patients. Despite extensive development and clinical testing, effective prophylactic and therapeutic vaccines against HSV infection have been elusive. Most vaccines that have been tested have been glycoprotein subunit vaccines (reviewed in reference 40). Vaccine candidates with novel adjuvants and T cell epitopes and replication-incompetent virus vaccines are currently in clinical trials for both therapeutic and prophylactic indications.

Additional data about the natural history of genital HSV-1 infection are needed to define efficacy of strategies for prevention of genital HSV-1 transmission. Similar to HSV-2, condom use, disclosure of genital HSV-1 infection and avoidance of sexual contact when oral or genital lesions are present are likely to be effective prevention strategies. Use of suppressive therapy to prevent HSV-1 transmission has not been studied.

PREVENTION OF NEONATAL HERPES All pregnant women should be screened for a history of genital herpes infection. If women have a clinical history of genital herpes, they may be placed on daily suppressive aciclovir at 36 weeks of pregnancy until delivery to reduce the risk of recurrent lesions that may prompt Cesarean section.38 There are no data to indicate that this approach reduces the risk of neonatal herpes, and cases occurring after maternal antiviral therapy in late pregnancy have been reported.39 At delivery, a

VACCINES

Clinical Features The presentation of genital herpes differs depending on whether it is first-episode genital herpes or recurrent infection. Only the minority of persons infected with HSV-2 will have classic presentations of genital ulcers; most have subtle signs and symptoms and therefore may not be accurately diagnosed. While the majority of lesions are present on the vulva or perianal area in women, or the penile shaft or perianal



Chapter 62  Genital Herpes

area in men, viral reactivation may occur throughout the innervation of the sacral ganglia. Thus, lesions may occur on the buttocks, thighs or lower abdomen. Clinicians must have a high index of suspicion for genital herpes and perform appropriate testing as described below.

CLASSIFICATION First-Episode Genital Herpes When patients present with their first genital herpes outbreak, they are considered to have first episode genital herpes. Patients with firstepisode genital herpes may lack antibody to HSV-1 or HSV-2 (primary infection), or may have nonprimary first-episode (heterologous HSV) antibody (e.g. HSV-1 antibody with acquisition of genital HSV-2), or first-episode with pre-existing antibody (e.g. HSV-2 antibody with first-episode genital HSV-2). It is important to note that most people acquire HSV-2 without identified genital symptoms; therefore, firstepisode genital herpes is due to previously acquired HSV-2 in over half of cases.41 The differing clinical manifestations of primary and nonprimary first-episode genital herpes are discussed below.

Primary Genital Herpes Persons who acquire genital herpes in the absence of antibody to HSV-1 or HSV-2 have primary genital herpes. The mean time from sexual contact to symptoms is 4 days (range 2–12). Symptomatic acquisition of primary genital herpes is typically the most severe manifestation of genital herpes in immunocompetent adults. Genital lesions start as singular vesicles or pustules; over a period of days these may coalesce to form very painful wet ulcers42 (Figure 62-4a). During the late vesicular wet ulcer stage, viral shedding and genital symptoms are at their peak. In primary infection, multiple, bilateral ulcerations may be present. The dry crust/healing stage is characterized by decreasing viral shedding, dry crust formation and re-epithelization of skin. Secondary groups of lesions may occur as initial lesions are healing. Lesions typically heal without long-lasting damage, although lesions on keratinized skin such as buttocks will occasionally scar. In the absence of antiviral therapy, lesions may take 3 weeks to heal after primary infection. Primary infection may also be characterized by local symptoms such as tender inguinal lymphadenopathy, cervicitis or proctitis and urinary retention. HSV proctitis may present with fever, burning rectal pain and tenesmus, perianal ulcerations and urinary

a

b

571

retention, and causes 25% of cases of proctitis in men who have sex with men.43 HSV cervicitis is associated with ulcerative lesions or the cervix may be diffusely friable.42 Systemic symptoms such as fatigue, malaise, myalgias and meningeal symptoms, which may be accompanied by viremia, are also frequent.

Nonprimary First-Episode Genital Herpes In nonprimary first-episode genital herpes symptoms are generally less severe than in primary herpes. Prior immunity to HSV-1 is associated with less severe first-episode infection of HSV-2,42 as prior immunity to the heterologous virus moderates the viral spread. Single or localized ulcers may be found, the duration of illness is shorter, and systemic symptoms are less pronounced. However, because of wide spectrum of severity in each category of first episode, an individual patient cannot be correctly classified based on clinical presentation alone, and viral detection as well as type-specific antibody tests are necessary to establish whether a clinical first episode represents new acquisition or reactivation.

Recurrent Genital Herpes Persons with established genital HSV-2 infection have periodic recurrences of genital herpes. Patients with symptomatic primary infection have a median of five recurrences in the first year after infection, and then reach a steady state of a median of four recurrences per year.44,45 The variability in recurrence rates is high, with some persons never having clinically apparent recurrences, and others having >10 recurrences per year. The reasons for variability are not well understood. Recurrent genital herpes may present with viral prodrome, characterized by 1–2 days of itching, tingling, or pain, presumably due to the virus travelling down the nerve to the skin, prior to the onset of genital lesions. Recurrent genital herpes often presents with a singular genital vesicle/ulceration which heals within a mean 3.9 days in men and 5.9 days in women in the absence of antiviral therapy (Figure 62-4b). Genital herpes recurrences may present with vague symptoms such as itching, tingling, or small ulcerations that patients do not identify to them as genital herpes. In addition, patients may mistake genital herpes recurrences for rash, folliculitis, or contact dermatitis.

c

Figure 62-4  Genital herpes. (a) Multiple perianal ulcers typical of primary genital HSV infection. (b, c) Evolution of a genital herpes recurrence. (b) A penile vesicle is present on day 1 of a recurrence. (c) The lesion evolves into a dry crust at day 4 of the recurrence.

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SECTION 2  Syndromes by Body System: Sexually Transmitted Diseases

Subclinical Acquisition and Infection As demonstrated in the placebo or control arms of HSV-2 vaccine trials, most genital HSV infections are acquired without symptoms. In one such study which enrolled 2393 high-risk persons, 57 (37%) of 155 HSV-2 acquisitions were symptomatic; the remaining 98 (63%) persons had subclinical seroconversion.46 Similarly, in the control arm of the Herpevac trial, which tested a glycoprotein-D2 subunit vaccine in HSV-1/HSV-2 seronegative women, 63% of HSV-2 and 74% of HSV-1 seroconversions were subclinical.47 Most HSV-2 seropositive persons in seroepidemiologic studies are not aware that they have HSV-2 infection. However, in prospective studies, nearly two-thirds of men and women with ‘asymptomatic’ HSV-2 infection report genital herpes outbreaks over a 3-month period after being educated about genital signs and symptoms of recurrent genital herpes.48 Therefore, most asymptomatic HSV-2 infected persons do recognize that they have the infection once they are made aware of signs and symptoms of genital herpes.

Subclinical Shedding An important feature of genital herpes infection is the frequency of subclinical genital shedding, when symptoms and lesions are absent but the virus can be transmitted. Such shedding during periods between recurrences accounts for about 50% of the time that the virus is present on the genital skin and mucosa.20

Extragenital Infection Meningitis.  HSV-2 may cause recurrent aseptic meningitis, characterized by fever, headache and stiff neck, and is probably the main cause of benign, recurrent, lymphocytic meningitis (‘Mollaret’s meningitis’). This may or may not be accompanied by a genital herpes outbreak.49 In a series of 40 persons with HSV-2 meningitis, nearly half had confirmed or suspected neurologic recurrence during a one-year follow-up.50 Pharyngitis.  Pharyngitis can occur in the setting of acquisition of oral herpes or both oral and genital herpes. In one series of >600 college students presenting with upper respiratory complaints, 6% had HSV isolated, predominantly HSV-1. Almost all had the clinical diagnosis of pharyngitis which was not distinguishable clinically from other causes of pharyngitis.51

Recurrences in Immunocompromised Hosts Recurrences in immunocompromised hosts such as persons with acquired immunodeficiency syndrome (AIDS) may be more frequent, prolonged or atypical as compared to immunocompetent hosts. Prolonged genital ulcerations due to HSV-2 were one of the first recognized manifestations of the AIDS epidemic (see Chapter 94). Genital ulcers may persist despite antiviral therapy, and antiviral resistance is more likely to develop in immunocompromised patients. AIDS patients may present with hypertrophic lesions in atypical locations mimicking squamous cell carcinomas in rare cases.52

Genital HSV-1 Primary genital HSV-1 infection causes disease of similar severity as primary genital HSV-2.42 However, the natural history of genital HSV-1 is less severe than for HSV-2, with a median of one outbreak in the year following primary infection,53 as compared to four for genital HSV-2.44 Risk factors for acquisition of genital HSV-1 include oral–genital and vaginal sex, and younger age. Men who have sex with men and heterosexual women are at increased risk.54,55

DIFFERENTIAL DIAGNOSIS The differential diagnosis of genital herpes includes other causes of genital ulcer disease, including syphilis, chancroid and lymphogranuloma venereum (LGV). However, the latter are unusual, with the exception of the recent resurgence of syphilis, and thus HSV is the predominant cause of genital ulcerations worldwide. Non-infectious causes of genital ulcers include fixed drug eruption, inflammatory bowel disease, or Behçet’s disease, which may present with oral ulcers

and uveitis. In addition, Candida, contact dermatitis, local trauma and folliculitis may mimic genital herpes recurrences. Unfortunately, neither history nor physical examination can definitively identify the cause of genital ulcers,46 and laboratory testing for the pathogen, or for antibody response, is required to assure accurate diagnosis and provide appropriate treatment.

HERPES IN PREGNANCY Women who acquire HSV during pregnancy are at the highest risk of complications of genital HSV infection. Primary infection during pregnancy may be associated with severe, disseminated infection characterized by HSV viremia, fulminant hepatitis and pneumonitis.56 Skin and mucosal lesions may be disseminated but may also be atypical or absent during the initial phase of the illness. In addition, acquisition of HSV-1 or HSV-2 during late pregnancy is associated with the highest risk of transmission to the neonate.57 The increase in risk appears to be confined to women who deliver prior to seroconverting to the newly acquired HSV, suggesting a potential role for transplacental antibody in protecting neonates from developing herpes. Neonatal HSV is acquired during passage through the birth canal, with increased risk of transmission with use of invasive monitoring during labor and delivery. Neonatal HSV is classified into isolated skin, eye and mucous membrane (SEM), central nervous system (CNS) and disseminated disease.58 Babies with neonatal HSV often present 3–20 days after delivery with non-specific fevers and fussiness, skin lesions are present in about 40% of cases, but may not be apparent at presentation; infants with CNS or disseminated disease may have seizures. Disseminated disease may present with sepsis often with pneumonia, or prominent liver involvement. SEM disease is associated with the best prognosis, and mortality in those with disseminated disease is 30%, even with use of appropriate, prompt antiviral therapy. Long-term cognitive impairment is common in infants with CNS disease.

Diagnosis

(see also Chapter 166) The clinical diagnosis of genital herpes infection has low sensitivity and specificity.46 Therefore, confirmation of the diagnosis using both direct virologic and serologic methods is desirable. The choice of test for diagnosis of genital HSV infection depends on the clinical presentation. For persons who have active genital lesions, a genital swab from the base of the ulcer should always be obtained for virologic diagnosis. If pustules or vesicles are present, these should be unroofed to obtain cells at the ulcer base. While viral culture has classically been the assay of choice for virologic diagnosis, the virus may not remain viable during transport, and low quantities may not grow well in culture. Furthermore, the virus may take up to 10 days to grow and cause cytopathic effect (CPE), which requires trained personnel to recognize. Modified viral cultures allow faster growth and more objective viral detection readouts. PCR using HSV-specific primers is four times more sensitive than viral culture, and is preferred when available.59 Commercially available PCR assays may decrease the cost and improve accessibility of viral PCR to practitioners. Both viral culture and PCR assays are able to distinguish between HSV-1 and HSV-2. Direct fluorescence antigen (DFA) tests have a rapid turnaround-time, but have low sensitivity and should not be used. In addition, Tzanck smears to look for multinucleated giant cells have low sensitivity and lack specificity for HSV infection and thus should be avoided. In rare cases when aciclovir-resistant infection is suspected, viral culture for phenotypic resistance to aciclovir should be performed, although genotypic testing is coming of age. For patients presenting without lesions and/or those presenting with first-episode genital herpes, type-specific serologic testing is recommended.29 The development and widespread availability of typespecific antibody testing represents a significant advance in understanding the epidemiology and management of genital HSV. The currently available assays use a variety of platforms including enzymelinked immunosorbent assays (ELISA), lateral flow and immunoblots



Chapter 62  Genital Herpes

TABLE 62-2 

573

Recommended Treatment Schedules for First-Episode and Episodic Genital Herpes, and Suppressive Antiviral Therapy for Genital Herpes Recurrences in Immunocompetent Adults

Drug

First Episode (Treat 7–10 Days)

Episodic

Suppressive Therapy

Aciclovir

400 mg TD, or 200 mg 5x/day

400 mg TD x 5 days, or 800 mg BD x 5 days or TD x 2 days

400 mg BD

Valaciclovir

1 g BD

500 mg BD x 3–5 days or 1 g BD x 5 days

500 mg QD or 1 g QD (if >9 recurrences/year)

Famciclovir

250 mg TD

125 mg BD x 5 days or 1 g BD x 1 day or 500 mg x 1 day then 250 g BD x 2 days

250 g BD

to exploit the type-specific IgG antibody response to glycoprotein G-1 and glycoprotein G-2. These assays have been validated to have a high sensitivity (93–96%) and specificity (94–97%) as compared to the gold standard University of Washington (UW) western blot.60 However, the Focus ELISA has a low positive predictive value,61 when an index value below 3.5 may represent a false positive, even though values around 1.1 are considered positive according to the manufacturer’s cutoff. The false positives occur more frequently in persons who also have HSV-1 infection, and who may have cross-reactive antibody. Western blot testing or Biokit should be used in situations where ELISA test results are not definitive. However, many practitioners currently rely on the Focus ELISA, and do not confirm the low positives. Serologic testing cannot distinguish between oral and genital infection. However, almost all people who are HSV-2 seropositive have genital herpes. In persons who do not have symptoms of oral or genital herpes, and who have HSV-1 antibody, the site of latency cannot be determined. In addition, serologic testing cannot typically determine when the infection was acquired, except in the case of primary infection when virus is detected from genital lesions and the HSV antibody test is negative. Seroconversion may take up to 12 weeks after infection. IgM antibody testing is never indicated in HSV disease as it is not type-specific and has low specificity for primary infection.62

Management COUNSELING As an incurable STI, genital herpes is a stigmatized infection. Patients diagnosed with genital herpes should be counseled about the nature of the infection, including asymptomatic shedding and transmission, expected frequency of outbreaks, risks including increased risk of HIV acquisition, lack of long-term health complications, risks associated with pregnancy in patient or partner, and therapeutic options. Education about genital herpes may decrease anxiety and help patients manage the infection.

ANTIVIRAL THERAPY (see also Chapter 153) The purine nucleoside analogs are the only antiviral medications approved by the US Food and Drug Administration to treat genital herpes infections. Aciclovir and its prodrug valaciclovir, and famciclovir, the prodrug of penciclovir, are guanosine analogs that are monophosphylated by the HSV-encoded thymidine kinase in virally infected cells. Cellular kinases complete the triphosphylation to acycloguanosine, which preferentially inhibits the viral DNA polymerase through selective uptake and chain termination.63 Since these antiviral agents are active only in cells infected with virus, they have a low toxicity profile and are generally well tolerated, with infrequent side effects of headaches and nausea. Intravenous aciclovir is used for severe cases of genital herpes and/or for neurologic disease, and may crystallize within the urinary collecting system; therefore, renal function must be monitored and adequate hydration must be given when aciclovir is given intravenously or when the patient has impaired renal function. Valaciclovir is the L-valine ester of aciclovir which provides greater bioavailability than aciclovir.64 The valine moiety is cleaved after

absorption and the levels of aciclovir that can be achieved with oral valaciclovir are higher than with oral aciclovir. Thus the advantage of valaciclovir is less frequent dosing. The approach to antiviral therapy depends upon which stage of the infection is being treated. Antiviral therapy is indicated in all firstepisode genital herpes infections, where it is associated with decreased duration of genital ulcers, pain and viral shedding.65 Oral aciclovir, famciclovir, and valaciclovir are recommended by CDC (Table 62-2). Given the excellent safety profile of these drugs, we do not recommend awaiting the confirmation of the diagnosis prior to initiating therapy because the infection can become more severe during that time. In severe cases of primary genital HSV infection, administration of higher-dose intravenous aciclovir may be required. Daily suppressive antiviral therapy is used to prevent recurrences and transmission in discordant sexual partnerships. Patients with genital herpes should be made aware of the option for use of suppressive therapy, which may be initiated at any time in the course of the infection, including after first-episode genital herpes.66 Suppressive therapy decreases the number of genital herpes recurrences, suppresses genital shedding by 70–80% and is associated with improved qualityof-life measures in those with recurrent genital herpes.64,67–69 Initiation of suppressive therapy should be based on patient preference rather than a number of recurrences per year. The need for suppressive therapy may be addressed with patients on an annual basis, but there is no need to interrupt therapy. There is no laboratory monitoring required for those on suppressive therapy, and the emergence of antiviral resistance is not associated with antiviral therapy in immunocompetent persons. Doses for suppressive therapy are shown in Table 62-2. Given that genital HSV-1 recurs infrequently after the first year of infection, suppressive therapy is not typically recommended. However, for outliers who have frequent genital HSV-1 recurrences, it is reasonable to offer suppressive antiviral therapy. Recurrent genital HSV-2 can be treated with episodic antiviral therapy, in which antiviral therapy is administered for 1–5 days at the first sign or symptom of a recurrence (Table 62-2). Episodic therapy decreases the length of the recurrence by ~1 day.70 Patients may or may not choose to treat the recurrences, depending upon how much discomfort they experience. If patients do desire treatment, antiviral therapy should be made available to them prior to the onset of symptoms, so that they are able to self-initiate therapy. While antiviral therapy has not been studied in clinical trials for genital HSV-1, similar efficacy as found in HSV-2 infection is likely, and it is reasonable to treat HSV-1 recurrences with antiviral agents. The efficacy of aciclovir, valaciclovir and famciclovir for treatment and prevention of genital herpes recurrences is similar. These antiviral agents have rarely been compared in head-to-head studies, but in one study suppressive famciclovir showed a shorter time to first virologically confirmed recurrence and a higher breakthrough shedding rate as compared to valaciclovir.71 Therefore, we typically use aciclovir or valaciclovir. However, all three drugs are equivalent for improvement in quality-of-life measures, and choice of drug may be related to patient preference, dosing intervals, cost and insurance coverage.72 Although the concepts of treating genital herpes with antiviral agents are similar for immunocompromised patients, the dosages and

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duration of therapy are increased.29 In addition, immunocompromised patients are at higher risk to develop aciclovir-resistant herpes, particularly after prolonged or inadequate exposure to antiviral agents; cross-resistance to valaciclovir and famciclovir is present and therefore these drugs should not be used. Intravenous foscarnet is the treatment of choice for aciclovir-resistant herpes, although this is a nephrotoxic medication that requires frequent laboratory monitoring.73 Management of patients with aciclovir-resistant herpes should be done in consultation with an infectious diseases specialist.

L-lysine supplementation is often used by patients due to perceived decrease in number of recurrences; however, this has not been borne out in clinical studies. Topical aciclovir is not effective for treatment of genital herpes. References available online at expertconsult.com.

KEY REFERENCES Bernstein D.I., Bellamy A.R., Hook E.W. 3rd, et al.: Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis 2013; 56(3):344-351. Bradley H., Markowitz L.E., Gibson T., et al.: Seroprevalence of herpes simplex virus types 1 and 2 – United States, 1999–2010. J Infect Dis 2014; 209(3):325-333. Corey L., Adams H.G., Brown Z.A., et al.: Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983; 98(6): 958-972. Corey L., Wald A.: Maternal and neonatal herpes simplex virus infections. N Engl J Med 2009; 361(14):1376-1385. Corey L., Wald A., Patel R., et al.: Once-daily valaciclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004; 350(1):11-20. Freeman E.E., Weiss H.A., Glynn J.R., et al.: Herpes simplex virus 2 infection increases HIV acquisition in men and

women: systematic review and meta-analysis of longitudinal studies. AIDS 2006; 20(1):73-83. Martin E.T., Krantz E., Gottlieb S.L., et al.: A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med 2009; 169(13):1233-1240. Mertz G.J., Jones C.C., Mills J., et al.: Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection: a multicenter double-blind trial. JAMA 1988; 260(2):201-206. Mertz K.J., Trees D., Levine W.C., et al.: Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities. The Genital Ulcer Disease Surveillance Group. J Infect Dis 1998; 178(6):1795-1798. Roizman B., Zhou G., Du T.: Checkpoints in productive and latent infections with herpes simplex virus 1: conceptualization of the issues. J Neurovirol 2011; 17(6): 512-517. Ryder N., Jin F., McNulty A.M., et al.: Increasing role of herpes simplex virus type 1 in first-episode anogenital

herpes in heterosexual women and younger men who have sex with men, 1992–2006. Sex Transm Infect 2009; 85(6):416-419. Tronstein E., Johnston C., Huang M.L., et al.: Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA 2011; 305(14):1441-1449. Wald A., Ashley-Morrow R.: Serological testing for herpes simplex virus (HSV)-1 and HSV-2 infection. Clin Infect Dis 2002; 35(Suppl. 2):S173-S182. Workowski K.A., Berman S.: Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010; 59(RR-12):1-110. Zhu J., Peng T., Johnston C., et al.: Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection. Nature 2013; 497(7450):494-497.

Chapter 62  Genital Herpes 574.e1

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