Version July 2025
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 do not have HIV infection.
This topic will review the epidemiology, clinical manifestations, and diagnosis of HSV-2 infection in people with HIV. The treatment of genital HSV in people 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 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 subsequently reactivates 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 similar 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 more than 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 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 HSV-2 replication. 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 immunosuppressed persons with HIV [9,35-37].
In a longitudinal study of 45 persons with HIV and HSV-2 infection, HSV shedding increased shortly after ART initiation but then decreased with time on ART [37]. In this study, rates of viral shedding were assessed through daily self-collected swabs over different periods of time. In persons not on ART, viral shedding was detected on 19 percent of days; this increased to 30 percent of days in those who recently initiated ART and subsequently decreased to 23 percent in those on ART for more than 90 days. Overall, HSV shedding decreased by 23 percent per year in those on prolonged ART. Genital lesions also declined after long-term ART use, from approximately 11 percent of days for untreated persons and persons recently initiating ART versus 5.5 percent of days after established ART.
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 —
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 infection, HSV-2-related genital ulcerations may range from painless ulcers [27,31,38] 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 [27,28,39]. 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) [19,40]. 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) [28,39,41].
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) [20,28,42-48]. 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 [20,28,48].
Hypertrophic lesions may also be found in ectopic locations including the orofacial area or the endobronchial tree [20,49,50]. Genital HSV-2 lesions mimicking HPV-related condyloma acuminata have also been described (picture 3) [51]. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis".)
Proctitis — HSV is a significant cause of proctitis among males with HIV. In a study of 179 patients presenting with proctitis in Australia, 36 percent were due to HSV-1 or HSV-2 in persons with HIV, compared to 19 percent in those without HIV [52].
The diagnosis HSV proctitis requires a high index of suspicion since visible external anal ulcerations may not be present. In one report, only 32 percent of people with HSV associated proctitis had visible external anal ulceration [53]. In some cases, severe herpes proctitis has been misdiagnosed as rectal adenocarcinoma [54]. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Clinical presentation'.)
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 [55,56]. However, herpetic lesions in atypical locations, such as the back, face or fingers (paronychia) [40] 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 'Preventing an immune reconstitution syndrome'.)
DIAGNOSIS —
A clinical diagnosis of genital herpes infection should be confirmed with diagnostic laboratory testing; this is particularly true in the individual with HIV where the clinical manifestations of disease may be atypical. The diagnostic approach is similar to that in patients without HIV [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 an open ulcer; 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. However, the commercial HSV antibody assays lack sensitivity for HSV-1 and specificity for HSV-2, and confirmatory testing may be required [57].
More detailed information on the performance of these various tests is found in a separate topic review. (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. 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 [58]. (See "HIV infection and malignancy: Epidemiology and pathogenesis".)
Surface samples of the lesion should be sent for HSV PCR testing; if PCR testing is not available, a viral culture may be sent. If laboratory testing is not diagnostic, 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 [44,47,48]. If treatment of documented HSV infection does not lead to resolution, drug-resistant HSV or an alternative diagnosis must be considered [59]. Dermatologic consultation and a skin biopsy are 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 [60]. Serologic testing performance varies by assay. Caution is suggested in interpreting low index value HSV-2 positive results, as false-positive tests can occur in both persons with and without HIV [61].
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 [62] and without HIV [1,63]. The differential diagnosis of genital ulcer disease, regardless of HIV status, includes other sexually transmitted diseases, such as syphilis and chancroid. Noninfectious etiologies include fixed drug reactions, Behçet's syndrome, neoplasms, and trauma. (See "Approach to the patient with genital ulcers", section on 'General approach'.)
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. (See 'Diagnosis' above.)
Mpox should also be considered in the differential diagnosis of people presenting with genital vesiculo-pustular or ulcerative lesions. In 2022, the mpox Clade II global outbreak was associated with genital lesions and proctitis that disproportionally affected men who have sex with men and persons with HIV infection. The vesiculo-pustular lesions seen in mpox may be less friable than HSV lesions, which are easily unroofed. (see "Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox)", section on 'Rash' and "Epidemiology, clinical manifestations, and diagnosis of mpox (formerly monkeypox)", section on 'Proctitis/tonsillitis')
The evaluation of patients who present with genital ulcers is presented in a separate topic review. (See "Approach to the patient with genital ulcers", section on 'General approach'.)
In patients with atypical manifestations or hypertrophic lesions or masses, 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 antiretroviral therapy [58]. (See 'Hypertrophic masses and pseudotumors' above and "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 [64]. (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) [65-67]. 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 'Preventing an 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 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 men with HSV-2 to women without HSV-2 [66,68,69]. 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 [70]. More detailed discussions of HSV-suppressive therapy in patients with HIV are found elsewhere. [71]. (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 individuals with HIV".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcer disease (GUD) worldwide. 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 infection with 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.)
●Epidemiology – Epidemiologic studies demonstrate that HSV-2 seroprevalence is disproportionately higher among persons with HIV compared to those without HIV. (See 'Epidemiology' above.)
●Natural history – The natural history of HSV-2 infection is altered among patients with HIV infection. Among patients with HSV-2, 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 subsequent HSV-2 transmission. (See 'Natural history' above.)
●Clinical manifestations – 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.)
●Evaluation and diagnosis – A clinical diagnosis of genital herpes infection should be confirmed with diagnostic laboratory testing; this is particularly true in persons with HIV in whom 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.)
●Screening – 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.)
The use of suppressive therapy and prevention of HSV-2 are discussed in separate topic reviews. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV" and "Prevention of genital herpes virus infections".)
