Version January 2024
INTRODUCTION — Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcer disease (GUD) worldwide [1-5]. Persons with HIV have a higher prevalence of HSV-2 infection, an increased risk of asymptomatic HSV genital shedding, and may have unusual clinical manifestations of HSV-2-related disease compared with HSV-2-seropositive patients who are HIV-uninfected.
This topic will review the epidemiology, clinical manifestations and diagnosis of HSV-2 infection in the HIV-infected host. The treatment of genital HSV in the host with HIV and the viral interactions between HIV and HSV-2 are discussed elsewhere. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV" and "Treatment of drug-resistant genital herpes simplex virus infection in patients with HIV".)
DEFINITIONS — The clinical designations of genital HSV infection are: primary, nonprimary first episode, and recurrent or reactivation disease (table 1). Among patients presenting with first episode of genital herpes, both virologic and serologic information is needed to accurately define the category of infection.
Primary — Primary infection refers to HSV infection in a patient without pre-existing antibodies to either HSV-1 or HSV-2.
Nonprimary — Nonprimary first-episode infection typically refers to the acquisition of genital HSV-2 in a patient with preexisting antibodies to HSV-1. The converse is rare because HSV-2 infection is thought to provide protection against genital HSV-1 infection. Most adults with HIV and a first episode of HSV-2 infection have nonprimary infection because of prior infection with HSV-1 [6,7].
Reactivation disease — Antiviral treatment during newly acquired infection lessens morbidity, but does not eradicate latent virus, which can subsequently reactivate in immunocompetent or immunocompromised hosts. Patients with a new diagnosis of HSV-2 infection should be counseled to expect recurrence of genital ulcers.
EPIDEMIOLOGY — There is a strong association between HSV-2 and HIV prevalence [8]. Epidemiologic studies demonstrate that HSV-2 seroprevalence is disproportionately higher among persons with compared to those without HIV with comparable demographic and behavioral risk factors for HSV-2 acquisition [8-16]. As examples:
●In a surveillance study of 3280 Peruvian men who have sex with men (MSM), a significantly greater proportion of males with HIV were coinfected with HSV-2 compared with males without HIV (81 versus 41 percent) [14].
●In a prospective cohort of 700 persons with HIV in the United States, 60 percent were HSV-2-seropositive, which is threefold higher than among the general United States population [16].
●Among 38,691 adults participating in HIV Prevention Trials Network 071 (PopART study), the odds of HIV infection were >6-fold higher in both males and females with HSV-2 infection [17].
NATURAL HISTORY
Clinical disease — The natural history of HSV-2 infection is altered among patients with HIV infection [18]. Among HSV-2 seropositive patients, concomitant HIV infection is associated with [19-23]:
●Increased frequency and severity of HSV-2 reactivation disease
●Atypical clinical manifestations of HSV-2 reactivation episodes
Among immunocompetent hosts, an average of four recurrences will occur during the first year after acquisition; recurrent genital lesions generally resolve within a median of four days with antiviral therapy [24]. In comparison with HIV-seronegative persons, genital HSV-2 recurrences in patients with HIV are more frequent and the episodes are of longer duration [25-28].
Persistent, non-healing lesions caused by HSV-2 are more common in patients with advanced immunosuppression (eg, CD4 cell counts less than 100 cells/mm3) [19,26], supporting the importance of cell-mediated immunity in controlling genital herpes. In addition, severe genital ulcers are associated with impaired HSV-specific CD8+ cytotoxic T-cell responses in persons with HIV [29]. (See 'Ulcerative disease' below.)
Viral shedding — HSV-2 is detected frequently from mucosal genital surfaces in the absence of genital ulcerative disease, referred to as “subclinical shedding” [30,31]. HSV-2 shedding is more frequent among males and females with HIV compared with those without HIV [21,27,32]. Among persons with HIV, the risk of HSV-2 shedding, as measured by polymerase chain reaction (PCR), is approximately six-fold greater in those with CD4 cell counts <200 cells/microL [33]. Increased rates of HSV-2 detection in the genital tract (using culture-based methods), are also associated with higher plasma HIV-1 RNA levels [34].
Effect of antiretroviral therapy on HSV-2-related disease — Small observational studies report conflicting results as to whether antiretroviral therapy (ART) ameliorates HSV-related ulcers and viral shedding among patients with HIV and immunosuppression [9,35,36]:
●In an observational study of 77 persons with HIV and recurrent disease, ART was associated with fewer days with genital ulceration (3 percent versus 11 percent of days); however, no significant change in the frequency or quantity of HSV-2 shedding was seen [35].
●In the Women’s Interagency HIV Study (WIHS), the frequency of genital ulcers did not change with the initiation of ART; genital HSV-2 shedding was not measured [9].
CLINICAL MANIFESTATIONS — As noted above, patients with HIV usually presents with HSV-related reactivation disease; the clinical manifestations are influenced by the patient’s current and prior immunologic status, as evidenced by CD4 cell counts [20,23]. (See 'Definitions' above.)
Ulcerative disease — In patients with well-controlled HIV disease, HSV-2-related genital ulcerations may range from painless ulcers [27,31,37] to typical shallow, erosive genital lesions approximately 2 to 7 millimeters in size. Symptoms of genital ulcers can include pain, tingling, and pruritus. Patients with ulcers near the urethra may complain of external dysuria. Others may have only subclinical shedding of virus without any mucocutaneous lesions, even during a careful examination [25].
However, in patients with AIDS, deep genital or perianal ulcerations or fissures have been described, which can be quite painful [27,28,38]. In the era prior to ART, chronic expanding ulcerative perianal lesions associated with HSV-2 infection were commonly observed among patients with severe immunosuppression (eg, CD4 counts <50 cells/mm3) [19,39]. Of note, persistent mucocutaneous HSV-2-related ulcers lasting greater than one month were among the first opportunistic infections to be classified as an AIDS-defining event (picture 1) [28,38,40]. These patients often had fever and weight loss related to other concomitant opportunistic infections [38].
Hypertrophic masses and pseudotumors — Atypical manifestations of HSV-2 infection described in patients with HIV include hypertrophic masses, pseudotumors, nodular, or plaque-like lesions, which may be mistaken for squamous cell carcinoma of the vulva, scrotum, or other malignancies (picture 2) [20,28,41-47]. Hypertrophic lesions are often observed among patients with advanced immunodeficiency (eg, CD4 counts <50 cells/mm3). This type of lesion can also be seen in a patient with a history of recurrent herpes and a low nadir CD4 cell count, despite ART-associated improvements in CD4 cell counts and HIV RNA suppression [20,28,47].
Hypertrophic lesions may also be found in ectopic locations including the orofacial area or the endobronchial tree [20,48,49]. Genital HSV-2 lesions mimicking condyloma acuminata secondary to human papillomavirus infection have also been described (picture 3) [50]. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis".)
Other unusual manifestations of HSV disease — More serious clinical presentations of HSV reactivation include esophagitis, tracheitis, meningoencephalitis, hepatitis, pneumonitis, retinal necrosis, and disseminated disease, which are rare among HIV-seropositive patients [51,52]. However, herpetic lesions in atypical locations, such as the back, face or fingers (paronychia) [39] do occur and thus HSV should be considered in the differential of cutaneous lesions outside of the genital area.
Severe genital ulcers may occur in patients starting on antiretroviral therapy as part of the Immune Reconstitution Inflammatory Response (IRIS). The prevalence of IRIS and its implications for treatment of HIV and HSV are discussed in detail elsewhere. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV", section on 'Immune reconstitution syndrome'.)
DIAGNOSIS — A clinical diagnosis of genital herpes infection should be confirmed with diagnostic testing; this is particularly true in the individual with HIV where the clinical manifestations of disease may be altered. The diagnostic approach is similar to that in the HIV-seronegative patient [25]. Techniques include polymerase chain reaction (PCR), viral culture, and type-specific serologic tests. Occasionally, a biopsy may be required, as discussed below.
Ulcerative disease — PCR-based testing is preferred for the diagnosis of HSV in a patient presenting with active lesions. Although both PCR and culture can determine the type of genital herpes (HSV-1 or HSV-2), PCR-based testing is much more sensitive than culture [25]. The diagnostic yield of either test is highest when the sample is taken from the base of a ruptured vesicle; the diagnostic yield declines rapidly as the lesion heals, especially for viral culture. Type-specific serologic testing to establish the presence of infection may be the preferred diagnostic test in patients with healing or small atypical lesions.
Details on the performance of these various tests are found elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Diagnosis'.)
Hypertrophic lesions — A high index of suspicion for HSV-2 infection is needed in patients with pseudotumors or hypertrophic lesions (herpes vegetans), which can be mistaken for papillomatous lesions or other genital pathology. Surface samples of the lesion should be sent for PCR testing; if PCR testing is not available, a viral culture may be sent. If laboratory testing is not informative, the lesion should be biopsied for examination for viral inclusions [28]. Histologically, these tumors may be characterized by pseudoepitheliomatous hyperplasia, which may be difficult to differentiate from squamous cell carcinoma [43,46,47]. Dermatologic consultation is advised if the diagnosis is uncertain.
Patients with a recent history of genital disease — Type-specific serologic testing may also be helpful in the patient with a history of recent genital ulcers who does not have any clinical findings on examination; antibodies to HSV-2 usually develop within 12 weeks after newly acquired infection [53]. Serologic testing performance varies by assay. Caution is suggested in interpreting low index value positive results, as false-positive tests can occur in both persons with and without HIV [54].
Routine serologic screening for HSV-2 in the asymptomatic patient is discussed below. (See 'Screening for HSV-2 infection' below.)
DIFFERENTIAL DIAGNOSIS — HSV-2 is the leading cause of genital ulcer disease in both persons with [55] and without HIV [1,56]. The differential diagnosis of genital ulcerative disease, regardless of HIV status, includes other sexually transmitted diseases, such as syphilis and chancroid.
Painful ulcers tend to be more typical of HSV and chancroid, while ulcers associated with syphilis, lymphogranuloma venereum (LGV), and granuloma inguinale are usually painless. HSV-related ulcers are also usually recurrent by history. However, a clinical diagnosis made solely on these distinctions may be misleading, emphasizing the importance of laboratory testing. Noninfectious etiologies include fixed drug reactions, Behçet’s syndrome, neoplasms, and trauma. (See "Approach to the patient with genital ulcers", section on 'General approach'.)
Routine diagnostic evaluation of a patient with genital ulcers includes HSV PCR (preferred if available) or culture for HSV and a screening test for syphilis, such as a rapid plasma reagin (RPR). The decision to test for chancroid will be influenced by epidemiologic risk factors, such as travel to an endemic area. (See "Approach to the patient with genital ulcers", section on 'General approach'.)
In patients with atypical manifestations or hypertrophic lesions or masses, the differential diagnosis is broad and includes a variety of dermatologic disorders of the genital skin and mucosa, such as HPV infection. Malignancy must also be considered in the differential diagnosis, since cancer is an increasing cause of morbidity and mortality among patients with HIV in the era of potent ART [57]. If treatment of documented HSV infection does not lead to resolution, drug-resistant HSV or an alternative diagnosis must be considered [58]. Dermatologic consultation and a skin biopsy may be required. (See "HIV infection and malignancy: Epidemiology and pathogenesis".)
SCREENING FOR HSV-2 INFECTION — Many providers do not routinely screen their patients with HIV for herpes simplex 2 (HSV-2) infection, regardless of CD4 count, due to perceived lack of benefit, lack of time for counseling, and risk of anxiety related to the diagnosis. The United States Preventive Services Task Force (USPSTF) recommends against screening asymptomatic immunocompetent individuals for HSV-2 [59]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Screening'.)
However, we typically screen persons with HIV infection and a CD4 count <250 cells/microL for HSV-2 prior to initiating antiretroviral therapy (ART), even if they are asymptomatic. Testing should be performed using HSV type-specific serology. For those with evidence of HSV-2 infection, we administer suppressive antiviral therapy for HSV-2 (ie, valacyclovir, acyclovir, famciclovir) for three to six months after ART initiation to reduce the risk of developing HSV-2-related genital ulcer disease as a manifestation of an immune reconstitution inflammatory syndrome (IRIS) [60-62]. More detailed discussions of HSV-2-associated IRIS and suppressive antiviral therapy for HSV-2 are found elsewhere. (See "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 type 2 in people living with HIV", section on 'Suppressive therapy'.)
HSV-2 serologic testing may also be reasonable for other patients as a way to inform counseling on how to reduce the risk of HSV-2 acquisition and transmission. As an example, condoms can reduce the risk of HSV transmission to an HSV-uninfected partner and may be particularly useful in preventing transmission from males with HSV-2 to females without HSV-2 [61,63,64]. By contrast, in patients with HIV who are not on ART, chronic suppressive antiviral therapy for HSV does not appear to prevent HSV-2 transmission to susceptible partners [65]. More detailed discussions of HSV-suppressive therapy in patients with HIV are found elsewhere. [66]. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV", section on 'Suppressive therapy' and "Prevention of genital herpes virus infections", section on 'Chronic suppressive therapy in discordant couples'.)
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" and "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)
SUMMARY AND RECOMMENDATIONS
●Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcer disease (GUD) worldwide. (See 'Introduction' above.)
●The clinical designations of genital HSV infection are: primary, nonprimary first-episode, and recurrent or reactivation disease. Nonprimary first-episode infection refers to the acquisition of genital HSV-1 in a patient with preexisting antibodies to HSV-2 or the acquisition of genital HSV-2 in a patient with preexisting antibodies to HSV-1 (eg, an individual with prior orolabial herpes and an HSV-1 antibody response develops genital herpes due to acquisition of HSV-2 infection). Most adults with HIV and a first-episode HSV infection have nonprimary infection because of prior exposure to HSV-1. (See 'Definitions' above.)
●Antiviral treatment during newly acquired infection lessens morbidity, but does not eradicate latent virus, which can subsequently reactivate in immunocompetent or immunocompromised hosts. (See 'Reactivation disease' above.)
●Epidemiologic studies demonstrate that HSV-2 seroprevalence is disproportionately higher among persons with compared to those without HIV. (See 'Epidemiology' above.)
●The natural history of HSV-2 infection is altered among patients with HIV infection. Among patients with HSV, concomitant HIV infection is associated with increased frequency and severity of genital ulcers. Advanced immunosuppression is associated with an increased risk of persistent non-healing ulcers and higher rates of subclinical viral shedding, which increases the risk of HSV-2 transmission. (See 'Natural history' above.)
●Clinical manifestations of HSV-2 infection vary according to the patient’s immunologic status. Genital ulcerations may range from unnoticed ulcers to typical herpetic lesions in the patient with well-controlled HIV infection to large, deep genital or perianal ulcerations in persons with advanced AIDS. Atypical presentations include pseudotumors or hypertrophic masses. (See 'Clinical manifestations' above.)
●A clinical diagnosis of genital herpes infection should be confirmed with diagnostic laboratory testing; this is particularly true in individuals with HIV where the clinical manifestations of disease may be altered. The diagnostic approach is similar to that in patients without HIV. Techniques include: polymerase chain reaction (PCR), viral culture, and type-specific serologic tests. The choice of test will vary depending on the clinical presentation. (See 'Diagnosis' above.)
●We typically screen patients with HIV and a CD4 count <250 cells/microL for HSV-2 prior to initiating antiretroviral therapy (ART) for HIV, even if they are asymptomatic. For those who are HSV-2 seropositive and are initiating ART, we administer suppressive antiviral therapy for HSV-2 (ie, valacyclovir, acyclovir, famciclovir) to reduce the risk of developing an HSV-associated immune reconstitution inflammatory syndrome. HSV-2 serologic testing is also reasonable for other patients with HIV as a way to inform counseling on how to reduce the risk of HSV-2 acquisition and transmission. (See 'Screening for HSV-2 infection' above.)
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