Treatment of genital herpes simplex virus type 2 in people living with HIV

INTRODUCTION — Genital herpes is a common sexually transmitted virus infection that is found worldwide. Genital herpes can be caused by either herpes simplex virus type 2 (HSV-2) or type 1 (HSV-1); most recurrences are caused HSV-2 as HSV-1 does not recur often in the genital area [1]. The seroprevalence of HSV-2 infections in people living with HIV is high (50 to 90 percent) [2] and genital ulcer disease can be more frequent, severe, and of longer duration than in patients without HIV [1].

This topic will review the treatment of genital herpes in people living with HIV. The treatment of genital herpes in persons without HIV and the epidemiology, clinical manifestations, and diagnosis of genital HSV infection in persons living with HIV are discussed elsewhere. (See "Treatment of genital herpes simplex virus infection" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus in patients with HIV".)

DEFINITIONS — There are three classification categories for genital herpes, as noted below.

Primary HSV infection — An HSV outbreak is defined as "primary" if the patient was HSV-seronegative for both HSV-1 and HSV-2 at the onset of genital lesions.

Nonprimary HSV infection — Nonprimary first-episode infection refers to the acquisition of genital HSV-2 infection in a patient with pre-existing antibodies to HSV-1 (eg, an individual with prior orolabial herpes). It is very rare to see acquisition of genital HSV-1 infection in a patient with pre-existing antibodies to HSV-2. Most people living with HIV with a new diagnosis of HSV infection have nonprimary disease due to prior acquisition of HSV-1 infection.

Reactivation (recurrent) disease — Antiviral treatment of newly acquired HSV-2 infection lessens morbidity, but does not eradicate latent virus, which can subsequently reactivate. In addition, some patients who have longstanding HSV-2 infection that has been asymptomatic can present with a first-recognized episode of genital herpes, especially in the setting of immunosuppression.

Compared with patients with HSV-2 infection and no HIV infection, people living with HIV have more frequent and severe recurrences, particularly those with advanced immunosuppression (eg, CD4 cell counts less than 100 cells/microL) [3,4]. HSV-2 reactivation episodes can range from painful ulcers to asymptomatic lesions, or viral shedding without any mucocutaneous erosions. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus in patients with HIV", section on 'Clinical manifestations'.)

AVAILABLE AGENTS — The nucleoside analogues acyclovir, valacyclovir, and famciclovir are the preferred antivirals for HSV infections. Each of these agents has been demonstrated to decrease pain, lesion duration, and viral shedding with comparable efficacy and safety among HIV-seronegative patients with primary and recurrent HSV-2 infection. The efficacy of these medications has also been evaluated in a number of clinical trials involving persons living with HIV [5-9]. (See 'Clinical trial data' below.)

These nucleoside analogs inhibit HSV DNA polymerase after being phosphorylated by virally-encoded thymidine kinase. This key phosphorylation step limits the activity of these agents to virally-infected cells, thus achieving a favorable side effect profile. (See "Acyclovir: An overview".)

Safety — Acyclovir, famciclovir, and valacyclovir have well-established safety records in people living with HIV; these drugs are generally well tolerated at the currently recommended doses. Adverse events can include nausea, diarrhea, or headache [10]. (See "Acyclovir: An overview" and "Famciclovir: An overview" and "Valacyclovir: An overview".)

In the past, high doses of valacyclovir (2 g four times daily) for the prophylaxis of cytomegalovirus infection were associated with thrombotic thrombocytopenic purpura (TTP) in people living with HIV; this syndrome has not been seen with the doses of valacyclovir currently used to treat genital herpes [11].

TREATMENT OF FIRST-EPISODE HSV INFECTION — The treatment of first-episode HSV infection in the person living with HIV is similar to the treatment in the immunocompetent host. However, clinicians should be aware that treatment of HSV-related disease in those with HIV should continue until all lesions have completely healed [10]. Most episodes of first-episode disease can be managed with oral agents, such as acyclovir, famciclovir, or valacyclovir; however, occasionally a patient with severe pain due to genital ulcerative disease or systemic symptoms, such as meningitis or bladder or bowel dysfunction, might require initial hospitalization for intravenous acyclovir therapy (5 to 10 mg/kg of bodyweight every eight hours) [10]. (See "Treatment of genital herpes simplex virus infection".)

Since most people living with HIV have acquired HSV-2 prior to the time of HIV diagnosis, most clinical management decisions are related to reactivation disease, as discussed below.

TREATMENT STRATEGIES FOR RECURRENT DISEASE — The principles of treatment of HSV-2 in people living with HIV are similar to those for persons without HIV. Management options of recurrent disease include chronic suppressive therapy or episodic therapy [10]. The decision to use episodic versus suppressive therapy is driven by patient preferences, and is discussed below. (See 'Which strategy to select' below.)

Suppressive therapy — This strategy involves the long-term administration of daily antiviral therapy to suppress symptomatic recurrences. (See 'Dosing guidelines for antiviral therapy' below.)

It was initially thought that there may be additional benefits to suppressive therapy for HSV in people living with HIV, such as reductions in HIV and HSV transmission to serodiscordant partners, and improvements in HIV outcomes. However, available data do not support these benefits. As examples:

●In patients without HIV, suppressive therapy for genital herpes reduces the risk of HSV transmission to an uninfected partner. However, this approach has not been found to be effective for people living with HIV who are not on antiretroviral therapy (ART) [12]. (See "Prevention of genital herpes virus infections", section on 'Effect on transmission'.)

●Despite the epidemiologic and biologic evidence for an association between HSV-2 and HIV infection (eg, HIV acquisition), HSV-2 suppressive therapy for people living with HIV has not been found to decrease the risk of HIV transmission [13].

●Although high-dose acyclovir therapy may have some benefit in preventing progression of HIV disease in patients not on ART [14], when suppressive valacyclovir was administered to patients receiving ART, there were no changes in T cell counts, markers of inflammation, or immune activation [15,16]. In addition, no additional improvements in HIV virologic outcomes were seen.

A more detailed discussion of preventing HSV transmission is found elsewhere. (See "Prevention of genital herpes virus infections", section on 'Chronic suppressive therapy in discordant couples'.)

Episodic therapy — This approach involves self-administered antiviral therapy for individual outbreaks as they arise. Patients are counseled to start therapy at the first sign of prodromal symptoms (eg, tingling, paresthesias, pruritus), which may occur prior to the onset of discrete lesions. Patients should be provided antiviral medication, as any delay in administration will attenuate the benefit of the intervention.

In patients without HIV, episodic therapy can be as short as one to five days. However, patients with HIV and HSV ulcerative disease should be treated for a minimum of five days or until lesion resolution, which can be significantly delayed among patients with advanced immunosuppression [5-9,17-19]. (See 'Episodic therapy' below.)

CLINICAL TRIAL DATA

General background — In people without HIV, acyclovir decreases the time to ulcer healing, the severity of symptoms, and amount of viral shedding compared with placebo [1]. The choice of antiviral agent depends largely on patient preference and cost; clinically, the drugs are thought to have similar efficacy for preventing or resolving HSV-related genital ulcers, as shown by multiple clinical trials in HIV-uninfected patients with recurrent genital ulcerative disease (GUD). (See "Treatment of genital herpes simplex virus infection".)

Limitations of clinical trial data — There are few placebo-controlled trials in people with HIV and HSV infection since the efficacy of acyclovir for HSV treatment was established many years ago among immunocompetent hosts. Thus, clinical trials of episodic therapy among people living with HIV have compared acyclovir with other antiviral agents within the same class (eg, famciclovir or valacyclovir). However, two clinical trials in people living with HIV did demonstrate the comparative benefit of suppressive therapy to placebo [8,9]. (See 'Suppressive therapy trials' below.)

There are no clinical trials comparing strategies of episodic versus suppressive therapy in people living with HIV and the clinical endpoints in the trials have varied. Also, several of these trials have used higher doses of antiviral medications for HSV than were used in the clinical trials among those without HIV [5,6].

The number of clinical events in each trial is also influenced by the level of immunosuppression among the study participants. Of note, most of the studies discussed below were performed prior to the era of potent antiretroviral therapy (ART).

Suppressive therapy trials — Three clinical trials have evaluated the role of suppressive antiviral therapy in the treatment of HSV recurrences among people living with HIV [6,8,9]. Of the two placebo-controlled trials, antiviral therapy reduced the number of recurrences and the duration of HSV-associated genital ulcerative disease [8,9].

Two trials were done prior to availability of combination ART:

●A 48-week double-blind clinical trial of suppressive HSV-2 therapy compared valacyclovir at two different doses (500 mg twice daily and 1 g once daily) to acyclovir (400 mg twice daily) in 1062 people living with HIV, 30 percent of whom had AIDS [6]. Valacyclovir dosed at 500 mg twice daily was associated with a similar time to onset of ulcer recurrence as acyclovir, while once-daily valacyclovir was inferior. Limitations of the trial included a 43 percent drop-out rate among the study participants (eg, loss of consent, protocol violations, loss to follow-up).

●In a double-blind trial, 48 HIV-1/HSV-2 coinfected persons were randomly assigned to receive famciclovir (500 mg twice daily) or placebo for eight weeks with subsequent cross-over to the other intervention arm; 63 percent of the patients had severe immunosuppression at enrollment and a significant proportion dropped out of the trial due to complications of end-stage AIDS [8]. Of the 29 patients who completed the cross-over portion of the trial, famciclovir led to a significant decline in the number of days with genital ulcers (14 percent versus 5 percent). Those assigned to the treatment arm also had a significant decline in HSV-2 shedding (11 percent versus 1 percent; RR 0.15; 95% CI 0.06-0.42).

Only one trial evaluated daily antiviral therapy for HSV in the era of combination ART:

●Valacyclovir (500 mg twice daily) was compared with placebo for the prevention of genital herpes over a six-month period in a 2:1 assignment of 293 study participants with a history of symptomatic genital herpes, 25 percent of whom had a CD4 cell count of <200 cells/microL [9]. More than 90 percent were taking three-drug combination ART and 50 percent had HIV suppression on enrollment. After six months of follow-up, significantly more subjects remained recurrence-free in the valacyclovir arm compared with placebo (65 versus 26 percent). The time to onset of first HSV recurrence also favored the valacyclovir arm compared with the placebo arm (>180 days versus 59 days).

Episodic therapy trials — Episodic therapy with famciclovir or valacyclovir appears comparable in efficacy to acyclovir in people living with HIV with a history of recurrent mucocutaneous disease [5-7]:

●In a double-blind clinical trial, 293 people living with HIV (approximately half of whom had CD4 counts <200 cells/microL) were randomly assigned to famciclovir (500 mg twice daily) or acyclovir (400 mg five times daily) for seven days [7]. Patients were followed serially for evaluation of new lesion formation on therapy and time to complete healing, symptom resolution, and cessation of viral shedding [7]. Famciclovir was equivalent to acyclovir for all of these parameters; new lesion formation during treatment occurred in 16 percent and 13 percent, respectively. Both treatments were well tolerated.

●In a subsequent trial, 639 people living with HIV (mean CD4 count 320 cells/microL) were randomly assigned to five days of valacyclovir (1 g twice daily) or acyclovir (200 mg five times daily) for recurrent genital herpes [6]. Similar rates of healing were noted in both arms among the 467 patients who did experience a recurrence. However, the trial fell short of the planned 900 study participants because of slow recruitment; thus the conclusions of the study are limited because the trial was underpowered. Patients in both treatment arms tolerated therapy well.

DRUG INTERACTIONS — There are no significant drug-drug interactions between these antiviral agents and HIV antiretroviral medications.

WHICH STRATEGY TO SELECT — There are few clinical trials comparing the efficacy of episodic and suppressive antiviral therapy for patients with recurrent HSV disease, regardless of HIV status (see 'Clinical trial data' above). Thus, we counsel patients about the general benefit of antiviral therapy for HSV compared with no intervention, and the relative advantages and disadvantages of either therapeutic approach:

●Suppressive therapy – Suppressive therapy for genital herpes decreases the number of recurrences by approximately 80 percent and is well tolerated, without a need for laboratory monitoring. As such, this approach should be discussed with all patients who have recurrent genital herpes, especially those with frequent, painful, or prolonged recurrences.

However, chronic suppressive therapy adds to the patient’s pill burden, and in people living with HIV not on antiretroviral therapy (ART), does not prevent HSV or HIV transmission to susceptible partners [12,13]. Whether suppressive therapy would prevent HSV-2 transmission in those living with HIV who are treated with ART is unknown. (See 'Suppressive therapy' above.)

●Episodic therapy – Episodic therapy is less costly and minimizes drug exposure. However, the clinical benefit is small, and therapy needs to be initiated at the first sign or symptom of a recurrence.

DOSING GUIDELINES FOR ANTIVIRAL THERAPY — In the 2021 Sexually Transmitted Disease guidelines, the Centers for Disease Control (CDC) made dosing recommendations for suppressive and episodic therapy for people living with HIV who experience HSV recurrences [19]. Several of these regimens use higher doses than those used among HIV-seronegative patients with HSV infection, based on the doses utilized in the clinical trial designs discussed above. Selection of any one particular antiviral agent should be driven mainly by cost and formulary considerations and frequency of dosing.

Although most patients can be managed with the oral regimens recommended below, patients with severe ulcerative disease or CNS involvement may require intravenous therapy initially with acyclovir (5 to 10 mg/kg every eight hours).

Suppressive therapy — For daily suppressive therapy, the CDC recommends any of the following regimens for the person living with HIV and recurrent HSV infection [19]:

●Acyclovir 400 to 800 mg orally twice daily to three times daily

●Famciclovir 500 mg orally twice daily

●Valacyclovir 500 mg orally twice daily

If using acyclovir, we generally start with the lower dose of 400 mg twice daily and increase to 800 mg twice daily if breakthrough recurrences occur. Of note, once-daily dosing of valacyclovir (500 mg to 1 g), which is used in immunocompetent hosts, has not been studied in people living with HIV [6].

Episodic therapy — For episodic therapy, the CDC recommends any of the following regimens [19], all of which are given for a minimum duration of 5 to 10 days, or until lesion healing:

●Acyclovir 400 mg orally three times daily

●Famciclovir 500 mg orally twice daily

●Valacyclovir 1 g orally twice daily

IMMUNE RECONSTITUTION SYNDROME — Immune reconstitution inflammatory syndrome (IRIS) related to HSV-2 infection is defined as either: (a) increased severity of ulcerative disease or (b) increased frequency of recurrences after the initiation of ART [20]. IRIS-associated genital herpes has been characterized by multiple genital ulcerations, which may be refractory to antiviral therapy, despite in vitro susceptibility to acyclovir [21,22]. The use of suppressive therapy in the first three to six months after antiretroviral therapy (ART) initiation may decrease the risk of HSV-2 genital ulcerative disease (GUD) and shedding, particularly for those with a low CD4 count [23]. In the United States, guidelines support the use of suppressive therapy to prevent genital ulcer disease in patients with a CD4 count <250 cells/microL who are starting ART [24]. (See 'Suppressive therapy' above.)

The incidence of IRIS-associated GUD due to HSV-2 has varied greatly in several observational cohorts, ranging from 9 to 50 percent [20,22,25-27]:

●In a retrospective cohort of 199 people living with HIV starting ART, 22 (50 percent) of 44 patients had IRIS related to anogenital HSV-2 infection, making it the most common manifestation of IRIS in this cohort [20]. Eleven (50 percent) of 22 patients with HSV-2 IRIS had a previous diagnosis of HSV-2; only two (9 percent) were receiving suppressive antiviral therapy at the time of ART initiation.

●In a cohort of 1551 people living with HIV in French Guiana, the risk of genital HSV-2 ulcers was 4.5-fold higher in the first two months after starting ART as compared with no ART, and remained elevated in the first six months after starting therapy [22]. After six months of ART, the rate of genital ulcers was equivalent to persons who were not receiving ART, suggesting that the risk of IRIS-associated genital ulcers is only transiently elevated.

HSV shedding appears to increase shortly after ART initiation, but decreases with time on prolonged ART. In one study that evaluated 45 persons with HIV and HSV-2 coinfection, HSV-2 shedding increased by 2.9-fold following ART initiation and subsequently decreased by 2 percent with each additional month on ART [28].

Although HSV shedding decreases with time, administering HSV-2 suppressive therapy when ART is initiated can decrease the risk of HSV-2-associated IRIS in patients with low CD4 counts. As an example, one randomized, placebo-controlled trial examined the effects of acyclovir 400 mg twice daily on progression of HIV infection in people with HSV-2 and HIV coinfection and not on antiretroviral therapy [23]. In this study, 132 patients initiated antiretroviral therapy when their CD4 count dropped to <250 cells/microL or when they received a diagnosis of WHO stage IV disease. The prevalence of GUD increased in the first three months following ART initiation (Prevalence Risk Ratio [PRR] 1.94, 95% CI 1.04-3.62) and returned to baseline after six months of ART. The risk of GUD was 58 percent lower among those who received acyclovir as compared with those who received placebo (PRR 0.42, 95% CI 0.23-0.74). Among a subset of 96 women who had a monthly genital shedding assessment, the risk of shedding increased in the first three months after starting ART (odds ratio [OR] 2.58, 95% CI 1.48-4.49) and returned to baseline levels by month six. Shedding frequency was decreased among those who received acyclovir compared to placebo (OR 0.13, 95% CI 0.04-0.41).

DURATION OF SUPPRESSIVE THERAPY — The safety of long-term therapy has been demonstrated in HIV-uninfected patients over six years of continuous treatment [29]. Once a patient has achieved immune reconstitution on ART, the number of HSV recurrences may diminish over time. Some experts recommend evaluating the ongoing need for suppressive antiviral therapy on an annual basis, particularly when the CD4 count is >200 cells/microL. However, some patients may desire continued suppressive therapy even after immune reconstitution due to concerns about HSV recurrence.

WHEN TO SUSPECT HSV DRUG RESISTANCE — If lesions continue to expand or do not heal on antiviral therapy, the clinician should suspect HSV drug resistance. Since acyclovir, valacyclovir, and famciclovir all share the mechanism of activity, resistance to one drug generally leads to cross-resistance to all medications within this class. The management of acyclovir-resistant HSV is discussed elsewhere. (See "Treatment of drug-resistant genital herpes simplex virus infection in patients with HIV".)

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 with HIV".)

SUMMARY AND RECOMMENDATIONS

●The seroprevalence of herpes simplex virus (HSV) type 2 infections in people living with HIV is high and recurrent disease can be more frequent, severe, and of longer duration than in HIV-seronegative patient populations. (See 'Introduction' above.)

●Antiviral treatment of first-episode HSV-2 infection lessens morbidity, but does not eradicate latent virus, which can subsequently reactivate. Clinical HSV recurrences are a common problem among people living with HIV, particularly those with advanced immunosuppression (eg, CD4 cell counts less than 100 cells/microL). (See 'Definitions' above.)

●The nucleoside analogues acyclovir, famciclovir, and valacyclovir have well-established safety and efficacy for treatment of genital HSV infections in people living with HIV; these drugs are generally well tolerated at the currently recommended doses. Because efficacy appears to be similar among these antiviral agents, selection of any one (eg, acyclovir, famciclovir, or valacyclovir) should be driven mainly by cost, formulary considerations, and frequency of dosing for patient convenience. (See 'Available agents' above and 'Safety' above.)

●The principles of treatment of HSV-2 in people living with HIV are similar to those for persons without HIV. We recommend antiviral therapy for all patients with first-episode genital HSV infection (Grade 1A). (See 'Treatment of first-episode HSV infection' above.)

●We recommend HSV antiviral therapy in people living with HIV who have clinical recurrences of HSV-2 infection (Grade 1B). Management options of recurrent disease include episodic therapy (eg, self-administered antiviral therapy for individual outbreaks as they arise) or suppressive therapy (daily administration of antiviral therapy for long-term maintenance). (See 'Treatment strategies for recurrent disease' above.)

●For patients with recurrent genital herpes, the choice of therapeutic strategy (ie, episodic versus suppressive therapy) should take into account efficacy of treatment, total pill burden (including antiretroviral medications), and history of disease severity. (See 'Which strategy to select' above and 'Duration of suppressive therapy' above.):

●Recommended doses of antiviral therapy are higher for both suppressive and episodic therapy for HSV recurrences in people living with HIV compared with patients without HIV; once-daily dosing has not been studied. In people living with HIV and HSV ulcerative disease, treatment should continue for a minimum of five days or until lesion resolution. (See 'Dosing guidelines for antiviral therapy' above.)

●The initiation of antiretroviral therapy (ART) for people living with HIV with advanced immunosuppression can lead to a paradoxical worsening of underlying HSV infection. Among patients with a CD4 cell count <250 cell/microL who have a history of genital ulcerative disease, we suggest coadministration of antiretroviral therapy for HIV and suppressive HSV antiviral therapy (Grade 2B). (See 'Immune reconstitution syndrome' above.)