Treatment of genital herpes simplex virus infection

INTRODUCTION — Genital herpes simplex is a common sexually transmitted virus infection that is found worldwide. Most of these genital infections are caused by herpes simplex virus-2 (HSV-2), but herpes simplex virus-1 (HSV-1) also produces a clinically similar disease, and the incidence of HSV-1 genital disease is increasing. Antiviral therapy can shorten the duration of symptoms and signs in primary infection, which, when untreated, can be associated with significant morbidity. Clinical recurrences are also common and can be treated episodically or prevented with continual antiviral suppression.

This topic review addresses the treatment of first and repeated episodes of genital herpes simplex infection. The epidemiology, clinical manifestations, and diagnosis of genital HSV infection and issues related to pregnancy are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection" and "Genital herpes simplex virus infection and pregnancy".)

TREATMENT OF FIRST EPISODE

Primary versus nonprimary infection — Patients with a first episode of genital HSV can have primary or nonprimary clinical infection. The approach to treatment of primary and nonprimary genital HSV infection is typically the same.

Primary and nonprimary infection are defined as follows:

●An HSV outbreak is defined as "primary" if the patient was HSV seronegative for both HSV-1 and HSV-2 before the episode of genital lesions. The primary episode of genital HSV infection can be associated with a multitude of constitutional symptoms and signs, such as fever, malaise, and headache. In addition to painful genital lesions, dysuria can be severe. Symptoms may last two to four weeks if left untreated. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)

●A nonprimary first episode of infection typically refers to HSV-2 infection in a person with pre-existing HSV-1 immunity [1]. The signs and symptoms of nonprimary infection tend to be less severe than primary infection. The impact of pre-existing HSV-2 immunity on HSV-1 genital infection is less clear; however, genital HSV-1 acquisition appears rare after HSV-2 infection [2]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Nonprimary infection'.)

A detailed discussion of the treatment of patients who have a first episode of genital HSV is found below. (See 'Indications' below and 'Regimen selection and duration' below and 'Consideration in complicated infection' below.)

Indications — In general, all patients experiencing a first episode of genital HSV should be treated with antiviral therapy [3]. Newly acquired genital HSV infection can cause a prolonged clinical illness with severe genital ulcerations even if the symptoms are mild at first. The one exception may be patients with nonprimary infection who present only with mild symptoms (eg, dysuria, sacral tingling) after several days.

Ideally, antiviral therapy should be started as soon as possible after lesion appearance and within 72 hours; many of the studies that evaluated the efficacy of antiviral therapy initiated treatment within this time period. However, antiviral therapy should still be offered if a patient presents with the ongoing development of new lesions and/or significant pain after this time frame. Regimen selection is discussed below. (See 'Regimen selection and duration' below and 'Consideration in complicated infection' below.)

Compared with untreated disease, oral antiviral therapy decreases the duration and severity of disease by days to weeks (particularly among those with primary infection) with minimal adverse drug effects [4,5]. However, treating the first episode of genital HSV does not eradicate latent virus [1,6,7]. Thus, all patients are at risk for recurrence and may require additional antiviral therapy. (See 'Treatment of recurrent infection' below.)

Acyclovir (200 mg orally [PO] 5 times daily for 10 days) was compared with placebo in a randomized trial of 150 patients with a first episode of genital HSV [4]. In the 119 patients with primary infection, acyclovir reduced the median duration of time to healing of lesions (12 versus 16 days), as well as the duration of local pain (five versus seven days), constitutional symptoms (three versus six days), and viral shedding (two versus nine days). However, in those with nonprimary infection, oral acyclovir only shortened the median duration of viral shedding and had no significant effect on the duration of lesions or symptoms. In a similar trial that included 48 patients with a first episode of genital herpes (including six with nonprimary infection), acyclovir reduced pain, length of time to healing, and duration of viral shedding [5]. In addition, antiviral therapy reduced the occurrence of new lesions 48 hours after treatment was initiated (4 versus 44 percent).

Antiviral therapy may also decrease the risk of complicated primary infection (eg, urinary retention). In a randomized study of 31 patients with a first episode of genital herpes and extensive genital lesions or systemic symptoms, patients received intravenous (IV) acyclovir or placebo for five days [8]. None of the patients who received IV acyclovir developed extragenital lesions or urinary retention requiring catheterization, compared with 4 of the 16 patients in the placebo group. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Extragenital complications'.)

Regimen selection and duration

General approach — Most patients with a first episode of genital HSV can be treated with oral therapy. IV acyclovir is typically reserved for the management of complicated infection (eg, central nervous system and disseminated disease). Topical therapy is of marginal benefit and should not be used [3]. (See 'Consideration in complicated infection' below and 'Role of topical therapy' below.)

The 2021 United States Centers for Disease Control and Prevention (CDC) guidelines recommend any of the following oral treatment options (doses based on normal renal function) [3]:

●Acyclovir: 400 mg three times daily

●Famciclovir: 250 mg three times daily

●Valacyclovir: 1000 mg twice daily

Therapy should be administered for 7 to 10 days. However, on occasion, a patient may continue to have new lesions even after completing a 10-day course. When this happens, we typically extend the course by five to seven days.

All three agents appear to have similar efficacy for the treatment of a first episode of genital herpes, and the margins of safety and tolerability are excellent [3,9-14]. We generally administer valacyclovir since it is dosed less frequently than the others, although oral acyclovir may be preferred in certain settings as it can be less expensive.

The efficacies of valacyclovir and acyclovir were compared in a multicenter randomized trial of 643 adults with a first episode of genital herpes, in which patients received 10 days of acyclovir (200 mg PO five times daily) or valacyclovir (1000 mg PO twice daily) [15]. There were no significant differences between the regimens in time to healing, duration of pain, time to clearance of all symptoms, and duration of viral shedding.

Famciclovir and acyclovir also have comparable efficacy for the treatment of a first episode of genital HSV. In three separate double-blind, controlled studies, which were conducted in a total of 951 patients (of whom one-third had primary HSV), several different dosing regimens of famciclovir (125, 250, 500, 750 mg) were compared with acyclovir for either 5 or 10 days [16]. In these trials, famciclovir was given three times daily, and acyclovir was given five times daily. Duration of shedding, median time to lesion healing, and time to resolution of symptoms were comparable among the famciclovir and acyclovir arms, except in the 10-day study, in which the 125 mg famciclovir arm was not as effective as the other doses.

No studies have directly compared valacyclovir and famciclovir for the first episode of genital HSV infection.

Consideration in complicated infection — Parenteral therapy should be initiated in patients with genital herpes infection accompanied by more severe clinical manifestations [3]. This includes:

●Central nervous system disease (eg, aseptic meningitis, encephalitis, or transverse myelitis)

●Sacral nerve involvement leading to urinary retention

●End-organ disease, including hepatitis or pneumonitis

●Disseminated HSV

The dose of IV acyclovir and the specific duration of therapy must be tailored to the specific clinical setting. As an example, in patients with sacral nerve involvement and urinary retention, IV acyclovir (5 to 10 mg/kg every eight hours) is administered for several days until clinical improvement is documented; the patient can then be transitioned to oral antiviral therapy to complete at least 10 days of therapy. However, longer courses of IV therapy are required for treatment of other conditions (eg, encephalitis) and may also be required for immunocompromised patients who have a more severe and protracted course.

More detailed information about acyclovir dosing can be found in the Lexicomp drug information monograph for IV acyclovir included within UpToDate, as well as in specific topic reviews. (See "Herpes simplex virus type 1 encephalitis" and "Acyclovir: An overview" and "Aseptic meningitis in adults".)

Adjunctive therapy — Some patients with a first episode of genital HSV experience moderate to severe local pain in the affected genital or sacral areas. Analgesics may be required in severe primary episodes with multiple painful lesions. Sitz baths are often helpful for women with severe dysuria secondary to multiple ulcerations.

Some women who have difficulty urinating may have developed urinary retention secondary to sacral nerve root involvement. In this clinical setting, either intermittent or indwelling bladder catheterization may also be required, usually for several days but occasionally extending beyond one week. Administration of pain medications prior to catheter insertion helps to decrease discomfort associated with the catheterization.

TREATMENT OF RECURRENT INFECTION

Risk of recurrence — Genital HSV infection often leads to frequent clinical recurrences, although the risk of genital recurrence is lower in those infected with HSV-1 versus HSV-2 [7]. Recurrences can occur even in those who were treated during their initial infection since treatment does not eradicate latent virus, which can subsequently reactivate [1,6,7]. Over time, recurrences due to either viral type generally decrease in number and severity, although there is substantial variability in the clinical course from patient to patient [6,17].

In the absence of suppressive antiviral therapy, the median recurrence rate after the first episode of HSV-2 infection is about four recurrences per year, with about 40 percent of patients having at least 6 recurrences and 20 percent having more than 10 recurrences in the first year [1,17]. By contrast, recurrences of HSV-1 occur approximately once per year.

With recurrent infection, the clinical manifestations of the lesions can also vary. Lesions can be asymptomatic, few in number, or atypical in appearance, especially in women (eg, fissures or vulvar irritation). In addition, the mean duration of lesions and duration of viral shedding appear shorter than those seen with the first episode (10 versus 19 days for duration of lesion and 2 versus 9 days for viral shedding) [4]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Recurrent infection'.)

These concepts were well illustrated in an observational cohort study of 664 immunocompetent patients with genital HSV-1 or HSV-2 infection who were followed for a minimum of 14 months; 306 had newly acquired infection [6]. Among patients with newly acquired genital herpes, the median rate of recurrence in the first year in patients with HSV-1 versus HSV-2 infection was one versus five per year, respectively. Second year rates were lower in both groups. Patients infected with HSV-2 who were followed for more than four years had a decreased recurrence rate over time, although about one-fourth of patients experienced an increase in recurrences at the five-year follow-up, highlighting the variability in disease course in those infected with HSV-2.

Treatment options — Oral antiviral therapy is often administered to patients with recurrent genital infection to reduce the severity of symptoms, decrease the risk of recurrences, and/or reduce the risk of transmission to an uninfected sexual partner. However, some patients may prefer not to take antiviral therapy, such as those with infrequent episodes and/or minimal symptoms, and especially those who are not sexually active. Similar to those with a first episode of genital HSV, there is no role for topical therapy. (See 'Role of topical therapy' below.)

For those who choose treatment, options include:

●Episodic therapy – Episodic therapy involves self-administered antiviral therapy for individual outbreaks as they arise. Patients start therapy at the very first sign of prodromal symptoms (eg, tingling, paresthesias, pruritus), which may occur prior to onset of discrete lesions. Episodic therapy modestly shortens the time to crusting and healing of lesions and also decreases the duration of viral shedding compared with placebo [18,19]. (See 'Episodic therapy' below.)

●Chronic suppressive therapy – This strategy involves administration of daily antiviral therapy and may be most appropriate for those with very frequent/severe recurrences and/or those who wish to reduce the risk of transmission to their HSV-uninfected sexual partner. Chronic suppressive antiviral therapy reduces the risk of HSV reactivation and decreases (but may not eliminate) shedding in patients with frequent recurrences [20,21]. (See 'Suppressive therapy' below.)

There are limited data on the optimal treatment strategy, and patient preference should be strongly factored into this decision. Although there may be some advantages to chronic suppressive therapy compared with episodic therapy (increasing the time to recurrence, reducing number of days with active disease), disadvantages include the need to take a daily pill. In addition, clinicians and patients alike need to be aware that viral shedding can occur despite complete absence of symptoms. A discussion of how to choose a treatment strategy is found below. (See 'Choosing a treatment strategy' below.)

The clinical benefits of suppressive versus episodic therapy were compared in a placebo-controlled trial of acyclovir in 156 patients with frequent recurrences (ie, more than six per year) [22]. In this trial, suppressive therapy with acyclovir (400 mg twice daily) was superior to episodic therapy (acyclovir 200 mg five times daily for five days) and placebo in increasing the median time to recurrence (250, 28, and 23 days, respectively) and reducing the median number of days per month with active disease (0.32, 4.18, and 4.72 days, respectively).

Quality of life measures also appear to be superior with chronic suppressive therapy [23,24]. This was demonstrated in a multicenter, open-label, randomized, crossover study evaluating the role of episodic therapy with valacyclovir (500 mg twice daily for five days) versus suppressive therapy (500 mg of valacyclovir once daily) in 225 patients who experienced a mean of approximately six recurrences per year [24]. In this study, the probability of developing a recurrence was 78 percent lower in patients assigned to the suppressive therapy arm compared with those in the episodic therapy arm, and no serious drug toxicity was reported over the 48-week period of the study. Of the 202 patients who completed the 48-week study, patient preference strongly favored suppressive versus episodic therapy (72 versus 28 percent). Treatment satisfaction (as measured by a disease-specific validated questionnaire) was based on various factors, such as perceived drug effectiveness, convenience, and lifestyle effects.

Choosing a treatment strategy — For most patients, our approach to determining a treatment strategy is based on the frequency of disease, the severity of symptoms, and the patient's level of concern about transmitting HSV to an uninfected partner. Special considerations in patients with HIV and those undergoing hematopoietic or solid organ transplant are presented elsewhere. (See 'Special considerations in patients with HIV' below and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Herpes simplex virus' and "Prophylaxis of infections in solid organ transplantation", section on 'Herpes simplex and varicella-zoster'.)

Our general approach is as follows:

●We suggest suppressive therapy for those with severe or frequent (≥6 recurrent episodes per year) recurrences. Although no study has explicitly examined the benefits of antiviral therapy based upon the frequency of recurrences, the randomized study described above found that suppressive therapy with acyclovir was superior to episodic therapy in patients with more than six recurrences per year [22]. (See 'Treatment options' above.)

We also suggest suppressive therapy for immunocompetent patients who want to reduce the risk of HSV transmission to an uninfected sexual partner, regardless of symptom severity. In a large randomized trial of 1484 immunocompetent, heterosexual, discordant couples, suppressive therapy led to a significant reduction in overall acquisition of genital HSV-2 infection in the uninfected partner (1.9 versus 3.6 percent, hazard ratio 0.52, 95% CI 0.27-0.99) [25]. (See "Prevention of genital herpes virus infections".)

●For patients with less frequent recurrences or moderately symptomatic disease, particularly those who are not sexually active, it is reasonable to administer episodic therapy. Patients with mild symptoms may choose no treatment at all.

However, the ultimate approach to treatment must be determined on a case-by-case basis, since patient preference should be strongly factored into this decision. As an example, compared with suppressive therapy, episodic therapy is not dependent on medication adherence to a daily regimen and may be less expensive [26]. Patients may also be concerned about the risk of toxicity with the use of suppressive therapy. Although studies of chronic suppressive therapy have not demonstrated a significant risk of these adverse outcomes, only a few studies have followed patients for ≥1 year [27,28].

Psychological aspects of recurrent genital HSV can also impact the approach to treatment of recurrent infection. In some patients who experience considerable anxiety or distress about their diagnosis, chronic suppressive therapy may be preferable, even in those with less frequent outbreaks. It is important to openly address these patient concerns and to offer counseling regarding the natural history of disease and transmission risk.

A potential concern with episodic or suppressive antiviral therapy is the emergence of clinical infection with acyclovir-resistant HSV-2. However, in immunocompetent patients, this risk is relatively rare [29-35]. In two large series, the rate was 0.18 and 0.32 percent, respectively [32,33]. Even when drug-resistant HSV is isolated from immunocompetent patients, this virus, with rare exceptions, is cleared normally without adverse clinical outcomes.

Treatment regimens

Episodic therapy — When prescribing episodic therapy, the provider needs to determine which antiviral agent to use. In addition, patients need to be counseled regarding the optimal timing of when to initiate treatment.

Choice of agent — For patients who choose episodic therapy, we administered one of the following regimens recommend by the United States Centers for Disease Control and Prevention (CDC) (doses based on normal renal function) [3]:

●Acyclovir: 800 mg three times daily for two days; or 800 mg twice daily for five days

●Famciclovir: 1000 mg twice daily for a single-day duration; or 125 mg twice daily for five days; or 500 mg once, followed by 250 mg twice daily for two days

●Valacyclovir: 500 mg twice daily for three days or 1000 mg once daily for five days

All available antiviral therapies appear to be similarly efficacious [26,36]. Thus, when choosing a regimen, convenience and cost should be considered. Brief courses of antiviral medications offer improved patient convenience; however, some patients may prefer less frequent daily dosing and a longer duration of therapy. If cost is a significant issue, acyclovir is generally less expensive.

Several different trials have evaluated the efficacy of the different antiviral regimens compared with placebo. As an example, acyclovir modestly shortens the time to crusting and healing of lesions and also decreases the duration of viral shedding compared with placebo [18,19]. This was demonstrated in a study in which 131 patients with recurrent infections were randomly assigned to 800 mg of acyclovir three times daily for two days or placebo; treatment was begun within 12 hours of first signs or symptoms [19]. Compared with placebo, acyclovir was associated with more rapid healing of lesions (four versus six days) and decreased duration of viral shedding (25 versus 59 hours). Acyclovir therapy was also associated with a higher proportion of aborted clinical HSV episodes (ie, those lesions never progressing past a papule). Similar efficacy has been reported with 800 mg three times daily for two days, 200 mg five times daily for five days, or 800 mg twice daily for five days [19,37]. However, 800 mg twice daily for five days appears to have greater efficacy than 200 mg five times a day in men even when initiated after the prodromal period [37].

Valacyclovir shortens healing time and accelerates resolution of pain by one to two days compared with untreated disease [38,39]. Three days of treatment with valacyclovir was also found to be equivalent to five days of valacyclovir in terms of healing, viral shedding, and lesion abortion [40,41].

The efficacy of famciclovir for recurrent episodes of genital HSV was illustrated in a multicenter trial of patient-initiated treatment with either famciclovir (125, 250, or 500 mg twice daily for five days) or placebo [42]. Subjects were instructed to perform cultures and to start therapy within six hours of lesion or symptom onset. Compared with placebo, each famciclovir dose produced a significant acceleration in cutaneous healing and symptom resolution (by approximately one day) and cessation of viral shedding (by approximately two days). There was no difference with respect to lesion healing among the famciclovir dosage arms. A subsequent randomized controlled trial demonstrated that a two-day short-course regimen of famciclovir (500 mg initially, then 250 mg twice daily) was noninferior to five days of famciclovir [26].

The efficacy of a shorter course of famciclovir (two 1000 mg doses on a single day) was evaluated for episodic treatment of genital HSV in immunocompetent patients [43]. In this multicenter, double-blind, placebo-controlled trial of 329 patients, famciclovir resulted in a faster median healing time compared with placebo (4.3 versus 6.1 days) [43]. Furthermore, the proportion of patients with aborted lesions was greater in the famciclovir group than in the placebo group (23 versus 13 percent).

Few direct drug-to-drug comparisons have been conducted for the treatment of recurrent HSV. In one trial, 739 patients were randomly assigned to valacyclovir (500 mg orally [PO] twice daily) or acyclovir (200 mg PO five times daily) for five days at the time of the next recurrence [44]. There was no difference between the groups in the primary end point, which was the duration of all signs and symptoms, including lesion healing and pain and/or discomfort. Percentages of patients in whom all HSV cultures were negative were similar in the valacyclovir and acyclovir groups (59 and 54 percent, respectively). In patients with a positive culture before treatment, cessation of viral shedding was similarly rapid in both groups.

In a noninferiority study of 1179 adults with a history of recurrent genital HSV, single-day famciclovir (1000 mg twice daily) was compared with a three-day course of valacyclovir (500 mg twice daily) [45]. Mean time to healing of lesions was similar in both groups, and approximately one-third of patients in each treatment arm had aborted episodes. Both regimens were well tolerated.

When to initiate therapy — Treatment should be initiated within the first 24 hours if possible. This is easiest to achieve if the patient is given a supply of medication, and therapy is initiated by the patient at the first sign of recurrence. It is important to counsel the patient that symptoms of recurrence can include tingling or paresthesias prior to the development of discrete lesions. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Recurrent infection'.)

Initiation of treatment within a 24-hour time frame is associated with faster resolution of cutaneous lesions and clinical symptoms compared with treatment that is initiated later in the disease course [18,19,42]. As an example, one early study demonstrated that the greatest benefit of antiviral therapy was derived by patients who self-initiated therapy compared with those who started treatment within 48 hours of lesion appearance [18]. Subsequent studies of all three anti-herpes agents demonstrated that early initiation of therapy (within 24 hours of symptoms) leads to faster resolution of recurrent cutaneous lesions and clinical symptoms compared with placebo [20]. Earlier trials generally used five days of episodic treatment, while later trials evaluated the efficacy of shorter courses of therapy (ie, one to three days) to improve patient convenience.

Suppressive therapy — Several antiviral regimens can be used for chronic suppressive therapy. The need for ongoing suppressive antiviral therapy should be assessed on a regular basis.

Special considerations regarding the use of suppressive antiviral therapy in patients with HIV and those undergoing hematopoietic or solid organ transplant are discussed elsewhere. (See 'Special considerations in patients with HIV' below and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Herpes simplex virus' and "Prophylaxis of infections in solid organ transplantation", section on 'Herpes simplex and varicella-zoster'.)

Antiviral regimens — The 2021 CDC guidelines recommend the following oral treatment options (doses based on normal renal function) [3]:

●Acyclovir: 400 mg twice daily

●Famciclovir: 250 mg twice daily

●Valacyclovir: 500 mg once daily or 1000 mg once daily

We prefer valacyclovir 500 mg once daily for most patients; however, for patients with >10 recurrences annually, we use valacyclovir 1000 mg once daily. In a randomized trial of valacyclovir for suppression of recurrent genital herpes in 1479 immunocompetent patients with a history of >10 recurrences per year, 1 g of valacyclovir once daily was more effective than 500 mg daily in preventing or delaying recurrences [21].

One direct comparative study suggested a modestly increased efficacy of valacyclovir compared with famciclovir for suppressive therapy [46]. However, in a meta-analysis of 6158 immunocompetent patients from 14 randomized placebo-controlled trials, the efficacy of acyclovir (400 mg twice daily), valacyclovir (250 mg twice daily), famciclovir (250 mg twice daily), and once-daily valacyclovir (500 mg) were comparable [27]. In this study, suppressive antiviral therapy lowered the relative risk (RR) of developing at least one recurrence compared with placebo (RR of 47 percent, 95% CI 45-49 percent).

Follow-up — We discuss the need for ongoing suppressive antiviral therapy on an annual basis since the number of recurrences diminishes with time, whether or not antiviral therapy is administered [3,47]. In addition, there are limited data on the long-term risks and benefits of antiviral therapy. Although many patients have been on chronic therapy for over a decade, the safety of suppressive therapy has only been demonstrated in one study that followed 239 patients for over six years [28]. Additional information on the risk of recurrence and the clinical trial data evaluating suppressive antiviral therapy is found above. (See 'Risk of recurrence' above and 'Choosing a treatment strategy' above.)

Despite the lack of data, many patients choose to continue long-term treatment due to the relative safety of the antiviral agents and concerns about relapses during treatment interruptions. In one study of 71 patients who were treated with acyclovir for 12 months, symptoms recurred within four weeks of stopping therapy in 69 percent of patients [48].

SPECIAL CONSIDERATIONS IN PATIENTS WITH HIV — Patients with HIV may have prolonged or severe episodes of genital herpes and are at greater risk for developing drug-resistant HSV compared with immunocompetent hosts [32]. Although antiviral regimens for treatment of genital herpes are generally similar to those used for immunocompetent patients, the United States Centers for Disease Control and Prevention (CDC) recommends higher doses for suppressive therapy [3]. (See 'Suppressive therapy' above.)

Antiretroviral therapy (ART) to treat HIV can ultimately reduce the severity and frequency of genital lesions secondary to HSV; however, the clinical manifestations may worsen initially after initiation of ART due to an immune reconstitution inflammatory syndrome (IRIS). Some providers initiate suppressive therapy to prevent IRIS [3]. In patients with HIV, suppressive therapy should not be used to reduce HIV or HSV-2 transmission to susceptible sex partners.

More detailed discussions of the management of genital herpes in patients with HIV are presented 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" and "Prevention of genital herpes virus infections", section on 'Immunocompromised patients'.)

ROLE OF TOPICAL THERAPY — In general, there is no role for topical antiviral therapy in the treatment of genital herpes [3]. Although topical agents (eg, acyclovir ointment) are available, they are of marginal benefit. In an analysis that compared the results of three randomized trials in patients with primary genital HSV, the clinical and virologic effects of intravenous and oral acyclovir were greater than topical treatment in reduction of viral shedding, time to complete healing of lesions, and reduction of new lesion formation [49]. As an example, oral therapy reduced viral shedding by 80 percent, whereas topical therapy only reduced shedding by 55 percent; in addition, oral therapy reduced new lesion formation whereas topical therapy did not. In a separate study, there was no advantage of adding topical therapy to oral therapy [50].

INVESTIGATIONAL AGENTS — The use of pritelivir for the treatment of HSV-2 is under investigation. Pritelivir is an inhibitor of the HSV-2 helicase-primase complex and acts through a mechanism that is different from that of the nucleoside analogues acyclovir, valacyclovir, and famciclovir.

Pritelivir has been investigated in two clinical trials:

●In one trial, different doses of pritelivir were compared with placebo in 156 HSV-2-positive persons with a history of genital herpes [51]. The relative risk (RR) of viral shedding with pritelivir compared with placebo over a period of 28 days was 0.13 (95% CI 0.04-0.38) with the 75 mg daily dose and 0.32 (95% CI 0.17-0.59) with the 400 mg weekly dose. In addition, the percentage of days with genital lesions during this period significantly decreased in those receiving these doses of pritelivir (1.2 percent for both versus 9 percent for placebo).

●In a second trial, suppressive therapy with pritelivir (100 mg daily) was compared with valacyclovir (500 mg daily) using a randomized crossover design [52]. Ninety-one subjects with recurrent genital HSV-2 were enrolled. Individuals received 28 days of one drug, followed by 28 days of a washout period before starting the second drug. The trial was stopped early due to safety concerns from a separate animal study; only 74 subjects completed one treatment period, and only 56 completed both treatment periods.

In an intent-to-treat analysis, pritelivir was associated with significantly less viral shedding compared with valacyclovir (2.4 versus 5.3 percent of genital swabs were positive; RR 0.42, 95% CI 0.21-0.82). In addition, patients receiving pritelivir had fewer days with genital lesions (1.9 versus 3.9 percent; RR 0.40, 95% CI 0.17-0.96). Among those receiving pritelivir, one person developed urticaria, and statistically significant lower total blood lymphocyte counts (average 110 to 230 x 10⁶/L lower) and higher serum creatinine levels (between 0.03 and 0.05 mg/dL higher) were observed. However, these laboratory findings were not considered clinically relevant.

Clinical trials comparing pritelivir to foscarnet for treatment of acyclovir-resistant herpes in immunocompromised hosts are currently being conducted [53,54].

PATIENT COUNSELING — The goals of counseling the patient and their sex partners are to help the patient cope with their diagnosis, prevent transmission, and identify any concerns or misconceptions. Patients need to be educated about the natural history of their infection with emphasis on viral shedding and the potential for clinical recurrence and sexual transmission, even when asymptomatic. A more detailed discussion of counseling is presented in a separate topic review. (See "Prevention of genital herpes virus infections", section on 'Counseling and education'.)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Genital herpes (The Basics)")

●Beyond the Basics topics (see "Patient education: Genital herpes (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Causative agent – Genital herpes simplex is a common sexually transmitted virus infection that is found worldwide. Most of these genital infections are caused by herpes simplex virus-2 (HSV-2), but herpes simplex virus-1 (HSV-1) also produces a clinically similar disease, and the incidence of HSV-1 genital disease is increasing. (See 'Introduction' above.)

●First episode – For almost all patients experiencing a first episode of genital HSV, we recommend antiviral therapy (Grade 1B). Antiviral therapy decreases the duration and severity of disease by days to weeks with minimal adverse drug effects and reduces the development of new lesions. Ideally, treatment should be started within 72 hours of lesion appearance. (See 'Indications' above.)

•Most patients can be treated with oral therapy. We prefer oral valacyclovir (1000 mg twice daily for 7 to 10 days) rather than oral acyclovir or famciclovir. All three of these agents appear to have similar efficacy, and the margins of safety and tolerability are excellent; however, valacyclovir is dosed less frequently. (See 'Regimen selection and duration' above.)

•Parenteral therapy should be reserved for patients with severe clinical manifestations/complications (eg, sacral nerve involvement leading to urinary retention, hepatitis, meningitis). The ultimate dose of intravenous acyclovir and the specific duration of therapy should be individually tailored to the specific clinical setting. (See 'Consideration in complicated infection' above.)

●Recurrent infection – The approach to treatment for recurrent genital infection must be determined on a case-by-case basis since patient preference should be strongly factored into this decision. (See 'Treatment options' above and 'Choosing a treatment strategy' above.)

•Suppressive therapy – In general, we suggest chronic suppressive therapy (eg, daily valacyclovir) for the following groups (Grade 2B) (see 'Suppressive therapy' above):

-Those with severe or frequent (eg, six or more per year) recurrences

-Immunocompetent patients who want to reduce the risk of HSV transmission to an uninfected sexual partner

•Episodic therapy – Patients with less severe or frequent recurrences and those who are not sexually active may reasonably prefer episodic therapy (antiviral therapy for individual outbreaks started at the very first sign of prodromal symptoms) or no therapy at all. (See 'Episodic therapy' above.)

●No role for topical therapy – There is no role for topical antiviral therapy in the treatment of genital herpes since topical therapy is only of marginal benefit, and there does not appear to be any advantage of adding topical therapy to oral agents. (See 'Role of topical therapy' above.)

●Considerations for persons with HIV – Patients with HIV may have prolonged or severe episodes of genital herpes and are at greater risk for developing drug-resistant HSV compared with immunocompetent hosts. The treatment of genital herpes in patients with HIV is reviewed in detail elsewhere. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV".)