Dermatologic Manifestations of Herpes Simplex

Herpes simplex viruses (HSVs) are linear double-stranded DNA viruses that cause acute skin infections and present as grouped vesicles on an erythematous base. Rarely, these viruses can cause serious illness and can affect pregnancy, leading to significant harm to the fetus. Most infections are recurrent and tend to reappear at or near the same location. Herpes labialis is the most common infection caused by HSV type 1 (HSV-1), whereas genital herpes is usually caused by HSV type 2 (HSV-2). Other clinical manifestations of HSV infection are less common.

Intimate contact between a susceptible person (without antibodies against the virus) and an individual who is actively shedding the virus or with body fluids containing the virus is required for herpes simplex virus (HSV) infection to occur. Viral shedding occurs during the primary infection, during subsequent recurrences, and during periods of asymptomatic viral shedding. Contact during these periods must involve mucous membranes or open or abraded skin. Following exposure, the primary infection of HSV is established at the site of contact. Here, the viral envelope is fused with the cellular membranes of the skin and mucous membranes and HSV DNA is incorporated into the nucleus.[1]  HSV glycoprotein C protects the viral envelope and aids in viral entry.[2] Recognition of HSV DNA by Toll-like receptors results in the activation of the innate and adaptive immune systems and production of interferon gene products.[1] Viral suppression of host cell immune responses and subsequent evasion of the immune system is accomplished via a complex interplay between HSV virion protein products and the immune system. Specifically, the HSV protein, virion host shutoff (VHS), is produced in the early stages of infection to suppress host cell responses.[1] Additionally, glycoprotein C binds to complement C3b, inhibiting complement-mediated immunity and plays a role in inhibiting antibody neutralization.[2]  HSV then invades and replicates in neurons as well as in epidermal and dermal cells. Virions travel from the initial site of infection on the skin or mucosa to the sensory dorsal root ganglion, where latency is established. The latent state is established by silencing of the HSV genome in neurons, and reactivation can occur during periods of stress.

Viral replication in the sensory ganglia leads to recurrent clinical outbreaks. These outbreaks can be induced by various stimuli, such as trauma, ultraviolet (UV) radiation, extremes in temperature, stress, immunosuppression, surgical and laser procedures, or hormonal fluctuations. HSV-specific CD8+ T cells appear to play an important role in controlling recurrent infections and reactivation.[3] CD8+ T cells are primed and recruited by innate and adaptive immune responses during the primary infection. The chemokine receptors, CXCR3 and CCR10, have been found to be up-regulated in HSV-specific CD8+ T cells and may contribute to homing mechanisms and control of inflammation during periods of reactivation.[3]

HSV-1 reactivation occurs most efficiently from trigeminal ganglia (affecting the face and the oropharyngeal and ocular mucosae), while HSV-2 has a more efficient reactivation in the lumbosacral ganglia (affecting the hips, buttocks, genitalia, and lower extremities). The clinical difference in site-specific reactivation between HSV-1 and HSV-2 appears to be due, in part, to each virus establishing latent infection in different populations of ganglionic neurons.[4]

Herpes simplex virus (HSV) type 1 and HSV-2 are the causative agents of herpes genitalis, herpes labialis, herpes gladiatorum, herpetic whitlow, herpetic keratoconjunctivitis, eczema herpeticum, herpes folliculitis, lumbosacral herpes, disseminated herpes, neonatal herpes, and herpes encephalitis.[5] They have also been linked to some cases of erythema multiforme. In pediatric patients, HSV infection is associated with 18% of cases of erythema multiforme.[6] A febrile illness, exposure to UV light, trauma, upper respiratory infection, or emotional stress may trigger recurrent herpes labialis due to HSV-1.

The patient's geographical location, socioeconomic status, and age influence the frequency of HSV-1 infections. The highest prevalence of antibodies to HSV-2 occurs in female prostitutes, male homosexuals, and HIV-positive individuals.

Frequency

United States

Herpes simplex virus (HSV) type 1 infection is typically acquired by early childhood. The seroprevalence of HSV-1 in persons aged 14-49 years in the United States is 53.9%, based on data from the 2005-2010 National Health and Nutrition Examination Survey (NHANES).[7] Only about 30% of these individuals have clinically apparent outbreaks. The seroprevalence of HSV-2 in the United States is 15.7%, and more than 80% of these infections are either asymptomatic or unrecognized.[7, 8] Regardless, these individuals still have episodes of viral shedding and can transmit the virus. The seroprevalence of HSV-1 has declined approximately 7% from prior NHANES data. However, the seroprevalence of HSV-2 has remained stable after increasing between 1976 and 1980 and subsequently declining between 1988 and 2004.[8] Independent predictors of HSV-2 seropositivity include female sex, older age, non-Hispanic black race, and increased lifetime sex partners.[8, 9] Additionally, patients with prior sexually transmitted infections, such as chlamydia, gonorrhea, and syphilis, have higher rates of HSV-2 seroprevalence.[10] Newer data indicate that HSV-1 infections may account for more genital infections than previously thought. A retrospective review of genital HSV infection in college-age students revealed that HSV-1 accounted for 78% of isolates, suggesting a reversal in prior etiologic notions.[11]

International

Serologic evidence of HSV infection varies by country.[12, 13] The seroprevalence of HSV-1 is 78.4% in Germany, whereas, it is 42.7% in the Netherlands.[14, 15] A study of two cities in Italy on the prevalence of HSV-1 and HSV-2 from 2000-2014 showed a significant decline in the study population (14.5% decrease in women; 22% decrease in men) for HSV-1 infection and a decline in HSV-2 infection from 22.4% to 11.5%.[16] Similar findings have been seen in the United States. 

Worldwide, the seroprevalence of HSV-1 and HSV-2 is 67% and 11.3%, respectively.[17, 18] As in the United States, HSV-1 prevalence increases with advancing age worldwide. The highest prevalence of HSV-1 and HSV-2 appears to be in Africa.[17, 18]

In the developing world, HSV-2 is becoming a common cause for genital ulcer disease, especially in countries with a high prevalence of HIV infection.[19] International studies show seroprevalence in people co-infected with HIV being close to 90% for HSV-1 and up to 77% for HSV-2.[20]

Race

The seroprevalence of HSV-2 in the United States is approximately three-fold higher in non-Hispanic blacks as compared with non-Hispanic whites.[8] Seroprevalence is highest among older non-Hispanic blacks, affecting approximately 56% of patients aged 30-49 years.[8] In contrast, the seroprevalence of HSV-1 in patients aged 14-19 years has declined from 55.7% (between 1999 and 2004) to 39.6% (between 2005 and 2010) in the non-Hispanic black population, but it has remained stable, at approximately 58%, in the Mexican American population.[7] Additionally, the seroprevalence of HSV-1 in foreign-born patients in the United States is higher than in patients born in the United States[7]

Sex

The frequency of HSV-1 antibodies is slightly higher in females than in males (33.2% vs 27.1%).[7] In a study of more than 600 pregnant women, 63% were seropositive for HSV-1, 22% for HSV-2, and 13% for both, and 28% were seronegative. Nonwhite race and having had four or more sexual partners independently correlated with increased HSV-2 infection. Non-Hispanic white pregnant women had the highest percentage of seronegativity for both HSV-1 and HSV-2. However, this group had the highest risk of having a child with neonatal herpes, indicating their susceptibility for new HSV infection during their third trimester of pregnancy (when a mother is most likely to transmit infection to her neonate).[21]

Socioeconomic factors appear to play a substantial role as well. Seropositivity for HSV-2 has been shown to be as high as 88% in homeless women or women with unstable housing.[22] Associated risk factors in this population were alcohol use, heterosexual orientation, HIV infection, and lower income status.[22]

Age

Overall, the seroprevalence of HSV-1 and HSV-2 increase with increasing age. From 2005-2010, the seroprevalence of HSV-1 among patients aged 14-19 years was 30.1% and 63.6% among patients aged 40-49 years.[7] Similar trends exist for HSV-2 seroprevalence, with 1.2% of persons aged 14-19 years affected and 25.6% of those aged 40-49 years affected.[7] The frequency of HSV-1 infection in children also varies with socioeconomic status. Approximately, one third of children from families of lower socioeconomic status exhibit some evidence of HSV-1 infection by age 5 years. A retrospective review of HSV cases from pediatric dermatology clinics found the average age of presentation to be 6 years and 33% of patients presented at age 2 years or younger.[23] Approximately 40% of these children had a history of atopy and experienced six or more outbreaks per year.[23] Triggers included UV light exposure, cold weather, and systemic corticosteroids for asthma.[23]

For most people, herpes simplex virus (HSV) infections are temporary and resolve without detrimental sequelae; however, recurrence is common. The associated pain, paresthesia, and discomfort, as well as the psychosocial impact, of herpes simplex outbreaks cause significant morbidity to the individuals who are affected. Long-term sequelae (usually CNS) are more common with neonatal HSV infection than with other types of HSV infection. Scarring may occur from severe or superinfected lesions.

Mortality/morbidity

Severe complications may be associated with herpes simplex. This is especially true in females who are pregnant and in individuals with immunosuppression, who may develop disseminated infection and encephalitis.

Complications of HSV-1 infections vary based on the site of involvement and whether the patient is immunocompromised. HSV-1 infections of the oral mucosa result in gingivostomatitis in children and pharyngitis in adults. Reactivation of infections of the oral mucosa present as herpes labialis and are less severe than the primary infection. HSV-1 can also infect any cutaneous surface. Patients with Darier disease, atopic dermatitis, or mycosis fungoides may develop life-threatening eczema herpeticum (Kaposi varicelliform eruption). Organ transplant recipients and patients with HIV/AIDS may develop herpetic lesions that exhibit an unusual morphology. Additionally, HSV DNA has been associated with erythema multiforme in approximately 43% of cases.[24]

Ocular and neurologic sequelae of HSV-1 infection include conjunctivitis, blepharitis, keratitis, acute retinal necrosis, Bell palsy, and encephalitis. Herpes simplex keratitis is characterized by ocular pain and is a common infectious cause of unilateral vision loss.[25] Clinical manifestations of HSV-1 encephalitis include fever, headache, nausea, vomiting, seizures, confusion, and focal deficits.[26] Approximately 15% of hospitalized patients die from HSV encephalitis, and survivors have long-term disability affecting cognitive function.[26]

The most common complication of primary HSV-2 genital infection is bacterial superinfection. Extragenital complications such as urinary retention, aseptic meningitis, and proctitis can occur in patients with HSV-2. Urinary retention and aseptic meningitis occur more frequently in women. Proctitis due to HSV-2 occurs more commonly in men who have sex with men and accounts for approximately 15% of cases.[27] Additionally, HSV-1 and HSV-2 are more common in men with proctitis and HIV infection than in those without HIV infection.[28]

Individuals co-infected with HSV and HIV and who have herpetic mucosal lesions are more likely to transmit HIV during sexual contact. In studies, despite being compliant with highly active antiretroviral therapy (HAART) for treatment of HIV-1 infection, 30-50% of women co-infected with HSV-2 and HIV-1 were shown to have genital HIV-1 shedding at least once in a 3-month period. Studies also suggest that co-infection with HSV-2 may accelerate HIV disease progression by elevating the HIV viral load. A 2008 study by Baeten et al found that HSV suppressive therapy decreased genital and plasma HIV levels in women with HSV-2/HIV co-infection.[29]

Another serious consequence of HSV infection is transmission of the virus to a neonate by a mother who is infected.[30] Asymptomatic maternal shedding occurs approximately 7% of the time and is responsible for most neonatal HSV infections. The risk of HSV transmission to the newborn is as high as 30-50% from a mother who acquired a new HSV infection near the time of delivery. Among women who have acquired HSV infection before their third trimester of pregnancy, the risk of transmission is less than 1%. HSV infections in neonates are most commonly due to HSV-2 and most are acquired peripartum from exposure to lesions (or shedding virus) in the birth canal, although in utero and postpartum transmission can rarely occur. Transmission is estimated to occur at a rate of 1 case in 3500-5000 deliveries in the United States. Neonatal infection can cause long-term sequelae and even death.

Reported in 2019, HSV-1 has been implicated in the pathogenesis of Alzheimer disease. HSV-1 has been shown to cause intracellular accumulation of amyloid-β protein (Aβ), which is involved in the pathogenesis of Alzheimer disease.[31] Additionally, patients that are apolipoprotein E carriers who had IgM or high-IgG titers against HSV-1 have an increased risk of Alzheimer disease.[32]

Patients who are immunocompetent should be reassured that the disease does not cause serious harm. However, physical and psychological concerns must be validated, and appropriate counseling is warranted.

For patient education resources, visit the Sexual Health Center, Oral Health Center, and Skin Conditions and Beauty Center. Also, see the patient education articles Genital Herpes, Genital Herpes in Woman, Oral Herpes, and Eczema.

Primary infection with herpes simplex viruses (HSVs) is clinically more severe than recurrent outbreaks. However, most primary HSV-1 and HSV-2 infections are subclinical and may never be clinically diagnosed.

Orolabial herpes

Herpes labialis (eg, cold sores, fever blisters) is most commonly associated with HSV-1 infection. Oral lesions caused by HSV-2 have been identified, usually secondary to orogenital contact. Primary HSV-1 infection often occurs in childhood and is usually asymptomatic.

Primary infection

Symptoms of primary herpes labialis may include a prodrome of fever, followed by a sore throat and mouth and submandibular or cervical lymphadenopathy. In children, gingivostomatitis and odynophagia are also observed. Painful vesicles develop on the lips, the gingiva, the palate, or the tongue and are often associated with erythema and edema. The lesions may progress to form pustules and ultimately ulcerate with a scalloped border, healing within 2-3 weeks.

Recurrences

The disease remains dormant for a variable amount of time. HSV-1 reactivation in the trigeminal sensory ganglia leads to recurrences in the face and the oral, labial, and ocular mucosae. Pain, burning, itching, or paresthesias usually precedes recurrent vesicular lesions that eventually ulcerate or form a crust. The lesions most commonly occur on the vermillion border, and symptoms of untreated recurrences last approximately 1 week. Recurrent erythema multiforme lesions have been associated with orolabial HSV-1 recurrences. A 2006 study reported that HSV-1 viral shedding had a median duration of 48-60 hours from the onset of herpes labialis symptoms. They did not detect any virus beyond 96 hours of symptom onset.[33]

Genital herpes

HSV-2 is identified as the most common cause of herpes genitalis. However, HSV-1 has been increasingly identified as a causative agent of primary genital herpes infections, and these are likely secondary to orogenital contact. HSV-1 accounts for 33% of primary genital herpes infections and is more common in patients younger than 30 years, those of white race, and men who have sex with men.[34] Recurrent genital herpes infections are almost exclusively caused by HSV-2.

Primary infection

Primary herpes genitalis occurs within 2 days to 2 weeks after exposure to the virus and has the most severe clinical manifestations. Symptoms of the primary episode typically last 2-3 weeks.

In men, painful, erythematous, vesicular lesions that ulcerate most commonly occur on the penis, but they can also occur on the anus and the perineum. In women, primary herpes genitalis presents as vesicular/ulcerated lesions on the cervix and as painful vesicles on the external genitalia bilaterally. They can also occur on the vagina, the perineum, the buttocks, and, at times, the legs in a sacral nerve distribution. Associated symptoms include fever, malaise, edema, inguinal lymphadenopathy, dysuria, and vaginal or penile discharge.

Females may also have lumbosacral radiculopathy, and as many as 25% of women with primary HSV-2 infections may have associated aseptic meningitis.

Recurrences

After primary infection, the virus may remain latent for months to years until a recurrence is triggered. Reactivation of HSV-2 in the lumbosacral ganglia leads to recurrences below the waist. Recurrent clinical outbreaks are milder and often preceded by a prodrome of pain, itching, tingling, burning, or paresthesia.

Individuals who are exposed to HSV and have asymptomatic primary infections may experience an initial clinical episode of genital herpes months to years after becoming infected. Such an episode is not as severe as a true primary outbreak.

More than one half of individuals who are HSV-2 seropositive do not experience clinically apparent outbreaks. However, these individuals still have episodes of viral shedding and can transmit the virus to their sexual partners.

Other HSV infections

Localized or disseminated eczema herpeticum is also known as Kaposi varicelliform eruption. Caused by HSV-1, eczema herpeticum is a variant of HSV infection that commonly develops in patients with atopic dermatitis, burns, or other inflammatory skin conditions. Atopic dermatitis is associated with a breakdown in the skin barrier and immune dysregulation, which can lead to cutaneous infections, such as, eczema herpeticum. Cutaneous infections in patients with atopic dermatitis lead to increased emergency department utilization, and both pediatric and adult patients have higher odds of an HSV infection.[35] Children are most commonly affected by eczema herpeticum, and it is more commonly associated with younger age and black or Asian race.[36] Eczema herpeticum can be diagnostically challenging, and the mean time to diagnosis is approximately 4 days.[37] Both primary and secondary HSV infections can lead to eczema herpeticum, and there is a 26.5% recurrence rate observed.[37] A retrospective study of 180 hospitalized patients with atopic dermatitis found that fever on admission, a rash on the neck, and a vesicular eruption were the clinical features associated with eczema herpeticum and these patients had a longer hospital length of stay.[38]

Additionally, HSV infection can complicate other cutaneous diseases associated with a breakdown in the skin barrier, such as pemphigus vulgaris. A hospital-based study of 60 patients with pemphigus vulgaris found that the presence of hemorrhagic crusting and linear erosions were associated with HSV infection.[39]

Herpetic whitlow, characterized by vesicular outbreaks on the hands and the digits, was most commonly due to infection with HSV-1. It usually occurred in children who sucked their thumbs and, prior to the widespread use of gloves, in dental and medical health care workers. The occurrence of herpetic whitlow due to HSV-2 is increasingly recognized, probably due to digital-genital contact.

Herpes gladiatorum is caused by HSV-1 and is seen as papular or vesicular eruptions on the face, arms, or torsos of athletes in sports involving close physical contact (classically associated with wrestling).

Disseminated HSV infection can occur in females who are pregnant and in individuals who are immunocompromised. These patients may present with atypical signs and symptoms of HSV, and the condition may be difficult to diagnose.

Herpetic sycosis, a follicular infection with HSV, may present as a vesiculopustular eruption on the beard area. This infection often results from autoinoculation after shaving through a recurrent herpetic outbreak. Classically caused by HSV-1, there have been rare reports of relapsing beard folliculitis caused by HSV-2.[40]

Neonatal HSV

HSV-2 infection in pregnancy can have devastating effects on the fetus. Neonatal HSV usually manifests within the first 2 weeks of life and clinically ranges from localized skin, mucosal, or eye infections to encephalitis, pneumonitis, disseminated infection, and demise.

Most women who deliver infants with neonatal HSV had no prior history, signs, or symptoms of HSV infection. Risk of transmission is highest in pregnant women who are seronegative for both HSV-1 and HSV-2 and acquire a new HSV infection in the third trimester of pregnancy.

Factors that increase the risk of transmission from mother to baby include the type of genital infection at the time of delivery (higher risk with active primary infection), active lesions, prolonged rupture of membranes, vaginal delivery, and an absence of transplacental antibodies. The mortality rate for neonates is extremely high (>80%) if untreated.

Clinical herpes simplex virus (HSV) infections appear as clustered vesicles on an erythematous base. They often progress to pustular or ulcerated lesions with a scalloped border, and they eventually form a crust. HSV lesions tend to recur at or near the same location within the distribution of a sensory nerve. Systemic symptoms, such as fever, malaise, and acute toxicity, may accompany the lesions, especially in primary infections. Each condition has associated symptoms and clinical findings (see History).

Although HSV infections may occur anywhere on the body, 70-90% of HSV-1 infections occur above the waist. In contrast, 70-90% of HSV-2 infections occur below the waist.

Physical manifestations of HSV infections in patients who are immunocompromised are usually similar to those in healthy patients. However, larger lesions or necrotizing ulcers may occur, and widespread areas may be involved. Additionally, immunocompromised patients or those with HIV infection may present with vegetative tumorlike nodules.[41] HSV-2 is detected in 86% of mucocutaneous tumoral HSV and 97% of cases occur in the setting of immunosuppression.[42] The majority of these tumorlike HSV nodules occur in the anogenital region (76%) and they occur more frequently in men.[42]

Neonatal HSV may be difficult to diagnose because, often, no mucocutaneous lesions are present on physical examination. Respiratory distress, jaundice, and seizures may occur.

The most common complication of herpes simplex virus (HSV) infections is bacterial superinfection. In women with primary HSV-2 infection, aseptic meningitis is also common.

Significant complications, such as visceral and CNS dissemination and long-term sequelae, are rare and occur in patients who are immunocompromised or in cases of neonatal HSV.

Patients with AIDS who are treated with intravenous acyclovir may develop thymidine kinase–negative strains of HSV that are resistant to acyclovir. These patients may be successfully treated with intravenous foscarnet or cidofovir.

Babies born to mothers with genital HSV infection should be closely monitored for any signs of infection and promptly treated if signs of the disease develop. Preterm babies are at higher risk and HSV infection should be considered in preterm babies with a maternal history of HSV infection, prolonged rupture of membranes, and leukopenia.[43] Neonatal HSV infection has a mortality rate of more than 80% if untreated and a mortality/significant morbidity rate of approximately 50% even when treated.

The approach to the patient presenting with cutaneous features of herpes simplex virus (HSV) infection can sometimes be difficult, and laboratory testing can aid in the diagnosis. Additionally, age, immune status, and pregnancy should be considered in all patients presenting with features of HSV infection.

Multiple modalities are available that can aid in the diagnosis of herpes simplex virus (HSV) infection. A survey of 81 public health laboratories in 2016 found that 37,101 HSV tests were performed.[44] The criterion standard for the diagnosis of HSV infection is viral culture. Detection and typing of HSV can be completed by obtaining a viral culture from unroofed skin vesicles. Early in the course of recurrent infection, 80-90% of viral cultures of untreated lesions are positive, but the false-negative rate increases after 48 hours of lesion onset.

Polymerase chain reaction (PCR) assays have become more widely available for the detection of HSV DNA. Detection and differentiation between HSV-1 and HSV-2 can be accomplished rapidly with high sensitivity and specificity, ranging from 95-99%.[45, 46] In a study comparing viral culture and PCR, HSV was detected in 31% of viral culture specimens and 53% of PCR specimens.[47] The average time for viral culture was 3 days, in comparison to 4 hours with PCR.[47] This is especially important in cases of suspected CNS infection, and PCR has replaced viral culture as the diagnostic test of choice in such cases.[48]

In the office, a Tzanck smear can be performed as a rapid test for the diagnosis of HSV infection. A Tzanck smear is prepared by scraping the floor of the herpetic vesicle. The sample may be stained with a Giemsa stain, Wright stain, or a Papanicolaou stain and then evaluated under a microscope. The presence of multinucleated giant cells is indicative of HSV infection, although the findings are not specific for the type of herpes virus. Approximately 50% of the results are positive.

Direct fluorescent antibody (DFA) testing may be used on air-dried smears, and approximately 75% of the results are positive.

Serologic assays use HSV-specific glycoproteins for detection and typing. Point-of-care and laboratory-based studies are available for HSV-2, and detection rates range from 80-98%.[48] In the early stages of infection, false-negative results may occur.[48] Serologic assays to detect antibodies against HSV-1 and HSV-2 may be useful in identifying organ transplant recipients or pregnant women who may be at risk for HSV reactivation. Their use is also becoming more common for confirming infection and for testing partners or those with asymptomatic infection. Western blot assays are highly sensitive and specific, and they can be considered in patients with suspected false-positive test results.[48]

Depending on the clinical scenario, the virus may be isolated from cerebrospinal fluid (CSF), stool, urine, the throat, anogenital mucosa, the nasopharynx, and conjunctivae. HSV-1 DNA has also been detected in tears and saliva.[49]

Cells infected with herpes simplex virus (HSV) demonstrate ballooning and reticular epidermal degeneration, epidermal acantholysis, and intraepidermal vesicles. Intranuclear inclusion bodies, steel-gray nuclei, multinucleate giant keratinocytes, and multilocular vesicles may also be present. Epidermal necrosis and an inflammatory infiltrate of lymphocytes and neutrophils may be observed. Additionally, up to one third of biopsy specimens may contain eosinophils.[50]  Histologic examination alone is unable to differentiate between subtypes of HSV. Immunoperoxidase techniques may be used to distinguish HSV-1 and HSV-2 antigens in formalin-fixed tissue samples.

Most herpes simplex virus (HSV) infections are self-limited and treatment is not always indicated or necessary. However, antiviral therapy shortens the course of the symptoms and may prevent dissemination and transmission.

Intravenous, oral, and topical antiviral medications are available for treatment of HSV infection and are most effective if used at the onset of symptoms. Oral therapy can be given at the time of the episode or as long-term suppressive therapy.

Treatment of herpes labialis and herpes genitalis generally consists of episodic courses of oral acyclovir, valacyclovir, and famciclovir. Oral antiviral medications may be used (off label) as therapy for other uncomplicated HSV conditions (eg, herpetic whitlow), and the same doses as those used for herpes genitalis treatment are commonly recommended.

Complicated HSV infections, cutaneous and/or visceral dissemination, neonatal HSV infection, and severe infections in those who are immunocompromised should be treated promptly with intravenous acyclovir.

In patients who are immunocompromised and have recurrent HSV infections, acyclovir-resistant HSV strains have been identified, and treatment with intravenous foscarnet or cidofovir may be used.

The treatment of herpes simplex virus (HSV) infections depends on multiple factors, including the location and severity of the disease, immune status, pregnancy, primary or recurrent disease, and frequency of recurrences.

Management

Herpes labialis

Primary infection with HSV-1 commonly presents a gingivostomatitis in children. Treatment should be started within 72 hours of suspected primary HSV-1 gingivostomatitis. Treatment with acyclovir decreases the duration of fever, oral lesions, eating/drinking difficulties, and viral shedding.[51] The duration of oral lesions is reduced by 6 days in patients treated with acyclovir in comparison to those treated with placebo (median 4 d vs 10 d).[51] The duration of treatment for primary HSV-1 infection is 7-10 days.

Recurrences are typically less severe than primary infections and are often heralded by a prodrome of burning pain or stinging prior to the herpetic eruption. Episodic treatment should be initiated at the first sign of recurrence. Treatments with acyclovir, valacyclovir, and famciclovir have all been shown to reduce the duration of lesions by 1-2 days. A study of 701 patients comparing famciclovir to placebo showed a median time to resolution of 4-4.5 days in the famciclovir groups in comparison to 6.2 days in the placebo group.[52] The dosing of valacyclovir and famciclovir is less cumbersome and more convenient, and both offer greater bioavailability.

Episodic treatment for recurrent herpes labialis in immunocompetent patients is as follows:

• Acyclovir 200-400 mg PO 5 times a day for 5 days

• Valacyclovir 2000 mg PO every 12 hours for 1 day

• Famciclovir 1500 mg PO as a single dose

Episodic treatment for recurrent herpes labialis in HIV-infected/immunocompromised patients is as follows:

• Acyclovir 400 mg PO 3 times a day for 5-10 days

• Valacyclovir 1000 mg PO twice daily for 5-10 days

• Famciclovir 500 mg PO twice daily for 5-10 days

Long-term suppressive therapy should be considered in patients with frequent and severe infections, specifically patients with herpes-associated erythema multiforme or eczema herpeticum. Long-term suppressive therapy has been shown to reduce the number of recurrences and prolong the time to first recurrence.[53]

Long-term suppressive therapy for recurrent herpes labialis in immunocompetent patients is as follows:

• Acyclovir 400 mg PO twice daily

• Valacyclovir 500-1000 mg PO daily

Genital herpes

Genital herpes is a chronic disease characterized by intermittent recurrences. The majority of cases are caused by HSV-2, and, like HSV-1, the primary infection is typically more severe. On average, patients experience four recurrences per year and 38% of patients have six or more recurrences during the first year.[54] Approximately 90% of patients experience a recurrence in the first year and some have a prodrome of tingling, pain, or paresthesias.[54, 55] The duration of lesions and viral shedding is shorter in recurrent episodes of genital herpes. Lesions may be asymptomatic, and many patients may be unaware when transmission occurs.[48] Primary genital herpes infections are typically more severe and may last 3 weeks if untreated. Treatment with systemic antivirals helps to decrease the duration and severity of both primary and recurrent genital herpes, but it does not eliminate the virus. Thus, the chronicity of the disease and preventive strategies are important aspects of management.[48]

Treatment for primary infection of genital herpes is as follows:

• Acyclovir 200-400 mg PO 3 times per day for 7-10 days

• Valacyclovir 1000 mg PO twice daily for 7-10 days

• Famciclovir 250 mg PO 3 times per day for 7-10 days

Systemic antivirals may be given for episodic disease recurrence or as long-term suppressive therapy. Episodic treatment can be considered for patients with few recurrences and those who experience a prodrome of symptoms signifying the need for initiation of systemic antivirals. Patients with multiples recurrences (6 or more) per year and those with unaffected partners may benefit from long-term suppressive therapy. Long-term suppressive therapy leads to a 70-80% reduction in the frequency of recurrences and decreases the rate of transmission.[48] Valacyclovir administered as long-term suppressive therapy has been shown to reduce transmission by 48%.[56] Recommendations for the episodic treatment of genital herpes and long-term suppressive therapy in immunocompetent and immunocompromised patients have been developed by the US Centers for Disease Control and Prevention (CDC) and are summarized below.[48]

Episodic treatment of recurrent genital herpes is as follows:

• Acyclovir 400 mg PO 3 times per day for 5 days

• Acyclovir 800 mg PO twice daily for 5 days

• Acyclovir 800 mg PO 3 times per day for 2 days

• Valacyclovir 1000 mg PO daily for 5 days

• Famciclovir 125 mg PO twice daily for 5 days

• Famciclovir 1000 mg PO twice daily for 1 day

• Famciclovir 500 mg PO once, then 250 mg PO twice daily for 2 days

Episodic treatment of recurrent genital herpes in patients with HIV infection is as follows:

• Acyclovir 400 mg PO 3 times per day for 5-10 days

• Valacyclovir 1000 mg PO twice daily for 5-10 days

• Famciclovir 500 mg PO twice daily for 5-10 days

Long-term suppressive therapy for recurrent genital herpes is as follows:

• Acyclovir 400 mg PO twice daily

• Valacyclovir 500-1000 mg PO once daily

• Famciclovir 250 mg PO twice daily

Long-term suppressive therapy for recurrent genital herpes in patients with HIV infection is as follows:

• Acyclovir 400-800 mg PO 2-3 times per day

• Valacyclovir 500 mg PO twice daily

• Famciclovir 500 mg PO twice daily

Treatment with systemic antivirals leads to faster healing and resolution of symptoms by 1-2 days. Viral shedding is also reduced as a result of treatment. All of the systemic antivirals have similar efficacy. A study that compared famciclovir 1000 mg twice daily for a single day and valacyclovir 500 mg twice daily for 3 days found no difference in the reduction in healing time.[57] Similar results with regard to long-term suppressive therapy have been observed among the systemic antivirals.

Special considerations

Acyclovir-resistant HSV

Acyclovir resistance is not common but does occur at higher rates in immunocompromised patients.[58] Acyclovir resistance can be attributed to thymidine kinase mutations and confers cross-resistance among the antiviral nucleoside analogs (acyclovir, valacyclovir, famciclovir, and penciclovir).[58] Agents that inhibit HSV-DNA polymerase (foscarnet and cidofovir) can be used in cases in which acyclovir resistance is suspected. Acyclovir resistance should be suspected in cases with persistent lesions or recurrences in patients on treatment.[48] Treatment with either intravenous foscarnet or cidofovir is effective for such cases. Additionally, a compounded topical preparation of cidofovir 1% gel applied once daily for 5 days may be a useful adjunctive or alternative treatment.[48, 59, 60] Resiquimod is an agonist of Toll-like receptors 7 and - that has been studied in patients with recurrent genital herpes. Topical resiquimod 0.01% gel applied twice weekly for 3 weeks increased the number of days to healing by 6-8 days and was associated significantly more erythema and erosions in comparison with vehicle.[61]

Pregnancy

Transmission rates of HSV to neonates during pregnancy are low in women with nonprimary HSV infections, but they approach 50% in women with primary infections.[62] Routine screening for HSV in pregnancy is not indicated, and diagnostic testing should be performed in suspected cases of genital herpes.[62] Management of genital herpes in pregnancy is accomplished through careful history and physical examination, especially during delivery. Vaginal delivery can be performed in the absence of signs or symptoms of genital herpes infection.[48] However, cesarean delivery should be performed in women with primary or recurrent genital herpes at the time of labor to reduce the risk of neonatal transmission.[48] Systemic antivirals can be used safely during pregnancy and can reduce the need for cesarean delivery.[48] However, neonatal transmission is still possible.[48]

Suppressive therapy for recurrent genital herpes in pregnancy is as follows:

• Acyclovir 400 mg PO 3 times per day (starting at 36 weeks’ gestation)

• Valacyclovir 500 mg PO twice daily (starting at 36 weeks’ gestation)

Topical antivirals

Acyclovir is available as a 5% ointment or cream and can be applied 5-6 times per day for either 4 or 7 days for the treatment of herpes labialis or genital herpes, respectively. The cream formulation should be avoided in cases of genital herpes. The benefit of topical acyclovir in the treatment of herpes simplex infections is modest at best. Despite statistically significant benefits in clinical trials, clinically significant results are not appreciable. In a study that compared acyclovir 5% cream with vehicle in the treatment of herpes labialis, a reduction in the duration of recurrence by one half day was noted in the acyclovir group.[63] A combination of 5% acyclovir and 1% hydrocortisone is available and can be applied topically 5 times per day at the earliest sign of cold sore recurrence. It has been shown to prevent progression in comparison to acyclovir and placebo.[64] Penciclovir is another topical antiviral available as a 1% cream that can be applied every 2 hours for herpes labialis. The clinical efficacy of topical penciclovir is similar to topical acyclovir. Docosanol 10% cream is available over the counter and can be applied 5 times a day for up to 10 days. In a study that compared docosanol with placebo, the average resolution time was approximately 4 days, or 18 hours shorter than placebo.[65] As stated, topical treatments for herpes simplex are much less effective than systemic antivirals. The CDC recommends avoidance of topical antivirals, owing to a lack of clinical benefit.[48]  

Other cutaneous HSV infections

Localized cutaneous HSV infections may result from mucocutaneous or cutaneous contact with infectious sources. Herpes gladiatorum, herpetic whitlow, and other localized cutaneous herpetic infections can typically be managed with similar treatment strategies for primary and recurrent herpes labialis or genitalis.

Eczema herpeticum

Eczema herpeticum is an acute HSV infection that occurs in patients with chronic severe atopic dermatitis. It is characterized by erythematous vesicles, erosions, and crusting that occur in areas affected by atopic dermatitis.[66] Dissemination can occur and may be associated with fever, pain, and lymphadenopathy.[66] Prompt initiation of systemic antivirals is indicated.

Erythema multiforme

HSV is the most common cause of erythema multiforme, and recurrences of erythema multiforme parallel recurrences of herpes simplex. Long-term suppressive therapy can be used for patients with six or more episodes per year or for those with severe recurrences. Long-term suppressive therapy with acyclovir has been shown to suppress recurrences of erythema multiforme in approximately 60% of patients.[67] Dosing of systemic antivirals for recurrent herpes labialis or genitalis can be used, as the majority of evidence is derived from small studies and case reports.

Consult a dermatologist and an infectious diseases specialist in cases of complicated or acyclovir-resistant herpes simplex virus (HSV) infections.

Avoidance of known triggers of herpes simplex recurrences, such as ultraviolet (UV) light and smoking, may diminish the number of outbreaks experienced by an individual.

Herpes simplex virus (HSV) viral shedding is greatest during clinically evident outbreaks; however, transmission from individuals who are seropositive to their partners who are seronegative usually occurs during asymptomatic periods of viral shedding. Therefore, preventing transmission requires more than abstaining from intimate contact during outbreaks.

The prevention of herpes labialis is focused on the avoidance of triggers and prophylaxis in certain scenarios. UV light exposure, specifically UVB, can lead to recurrences of herpes labialis, and sunscreen can help prevent recurrences.[68] Laser resurfacing has been shown to cause recurrences in 2.2% of patients, and prophylaxis with systemic antivirals may reduce the risk of recurrence.[69, 70]

Barrier methods, such as condoms, confer 10-15% protection against the transmission of genital herpes, as transmission can occur to and from uncovered mucocutaneous surfaces or if the integrity of the barrier is compromised. Condoms have also been shown to be more effective in protecting women than men.

Various HSV vaccines have been and continue to be under investigation for the treatment and prevention of herpes genitalis, although most have not been shown to be effective.[71] A trivalent glycoprotein C, D, and E vaccine has been evaluated in guinea pigs, and a 50% reduction in the frequency of recurrences and vaginal shedding of HSV was observed.[72] Double-blind randomized trials of a glycoprotein D HSV-2 vaccine revealed that the vaccine conferred protection against the virus in women who were serologically negative for both HSV-1 and HSV-2. However, it did not prevent HSV infection in men, despite their serostatus, or in women who were positive for HSV-1 but negative for HSV-2.[73] In 2017, a glycoprotein D monoclonal antibody that can block in vitro cell-to-cell spread of HSV was developed, with implications for the prevention and treatment of HSV infection.[74]

Long-term suppressive therapy for genital herpes has been shown to decrease asymptomatic HSV shedding, and long-term valacyclovir therapy significantly decreased HSV transmission to susceptible partners of individuals who were HSV-2 positive by 50-77%.[75] Acyclovir and famciclovir have been shown to be as effective as valacyclovir for suppression of recurrences. Considerations for placing a patient on long-term suppressive therapy include frequent and/or severe outbreaks, infection in a patient who is immunocompromised, the patient’s sex, the patient’s HSV serostatus, and the reproductive capability of the patient’s partner.

HIV infection of an HSV patient or his or her seronegative partner should also be considered a possible indication for suppression, given the proposed increase in HIV viral load, although HSV suppressive therapy has not been shown to have an effect on HIV-1 viral shedding.[76, 77, 78]

Women who are HSV-2 negative should be counseled to abstain from intercourse during the third trimester of pregnancy with partners who could be seropositive because primary HSV infection during this time places the fetus at highest risk of infection.

The most common approach in attempting to prevent vertical transmission is to have women with clinically apparent HSV lesions during labor undergo cesarean delivery. However, cesarean delivery does not prevent all cases of neonatal infection because in utero infection occurs and antepartum HSV cultures are not a good predictor of neonatal infections.

Use of acyclovir 400 mg PO thrice daily during the third trimester of pregnancy has been proven to be safe and effective in preventing neonatal herpes and in eliminating the need for cesarean deliveries.[79]

A large nationwide cohort study in Denmark did not find any association between first trimester in utero antiviral drug (ie, acyclovir, valacyclovir, famciclovir) exposure and congenital anomalies. In 1804 pregnancies exposed to an antiviral drug during the first trimester, 40 infants (2.2%) were diagnosed with a major birth defect, compared with 19,920 (2.4%) unexposed pregnancies.[80] A 2017 review also reports that prophylactic acyclovir reduces active genital lesions at delivery.[81]

The American College of Obstetricians and Gynecologists (ACOG) has released guidelines on expedited partner therapy for chlamydial and gonorrheal sexually transmitted diseases (STDs).[82, 83] While designed to prevent reinfection with chlamydia and gonorrhea, the recommendations can also be applied to other STDs. The ACOG recommendations include the following:

• Expedited partner therapy to prevent reinfection, with legalization of expedited partner therapy

• Counsel partners to undergo screening for HIV infection and other STDs

• Expedited partner therapy contraindicated in cases of suspected abuse or compromised patient safety; pretreatment evaluation for abuse potential recommended

• Expedited partner therapy medications and protocols based on CDC, state, and/or local guidelines

Guidelines from the CDC on sexually transmitted disease treatment are available.[48]  See 2015 Sexually Transmitted Diseases Treatment Guidelines.

Acyclovir is an analog of 2'-deoxyguanosine and, along with other nucleoside analogs listed below, remains the drug of choice for herpes simplex virus (HSV) infections. Antibiotics may be used if a secondary bacterial infection develops.

Class Summary

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV DNA polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Acyclovir topical

Acyclovir inhibits the activity of both HSV-1 and HSV-2. Patients experience less pain and faster resolution of cutaneous lesions when topical acyclovir is used within 48 hours from rash onset. It may prevent recurrent outbreaks. Acyclovir has been proven to be safe and effective in preventing neonatal HSV and in eliminating the need for cesarean deliveries.

Penciclovir (Denavir)

Penciclovir topical formulation is for use in mild recurrent herpes labialis. It is an inhibitor of DNA polymerase in HSV-1 and HSV-2 strains, inhibiting viral replication.

Famciclovir (Famvir)

Famciclovir is a prodrug that when biotransformed into its active metabolite, penciclovir, may inhibit viral DNA synthesis/replication.

Valacyclovir (Valtrex)

Valacyclovir is a prodrug that is rapidly converted to the active drug, acyclovir. Valacyclovir is more expensive but has a more convenient dosing regimen than acyclovir.

Foscarnet (Foscavir)

Foscarnet is an organic analog of inorganic pyrophosphate that inhibits the replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at the pyrophosphate-binding site on virus-specific DNA polymerases. Poor clinical response or persistent viral excretion during therapy may be due to viral resistance. Patients who can tolerate foscarnet well may benefit from initiation of a maintenance dose of 120 mg/kg/d early in treatment. Individualize dosing based on renal function status.

Cidofovir (Vistide)

Cidofovir is approved for the treatment of CMV retinitis. A compounded cream/gel (not FDA approved but recommended by CDC) formulation can be used for localized acyclovir-resistant HSV.

Docosanol cream 10% (Abreva)

Docosanol cream 10% is used for HSV-1 infections. It prevents viral entry and replication at the cellular level. It should be used at the first sign of a cold sore or fever blister.