Continuing Education Activity

This activity reviews the evaluation and management of herpes simplex type 2 and highlights the role of the primary care provider in managing patients with this condition. In addition to providing basic knowledge of the condition and clinical presentation of herpes genitalis, this review will highlight important aspects of the diagnostic interventions, antiviral therapy (both current and future), and prophylaxis. This activity covers the interprofessional team managing patients with herpes genitalis and with the potential of being exposed to herpes genitalis.

Objectives:

• Identify the etiology of herpes simplex type 2.
• Outline the appropriate evaluation of herpes simplex type 2.
• Review the treatment and management options available for herpes simplex type 2.
• Describe interprofessional team strategies for improving care coordination and communication to advance herpes simplex type 2 and improve outcomes.

Introduction

Herpes genitalis can be caused by the herpes simplex virus type 1 or type 2 and manifests as either a primary or recurrent infection.[1]  Most commonly, viral replication occurs in epithelial tissue and establishes dormancy in sensory neurons, reactivating periodically as localized recurrent lesions.[2]  It remains one of the most common sexually transmitted infections (STI) but continues to be underestimated, given the vague presentation of its symptoms.[3] In addition to providing the reader with basic knowledge of the pathogen and clinical presentation of herpes genitalis, this review article discusses important aspects of the laboratory diagnostics, antiviral therapy, and prophylaxis. This article is aimed at all health-care providers managing patients with herpes genitalis and attempts to improve the often suboptimal counseling, targeted use of laboratory diagnostics, treatment, and preventive measures provided to patients.

Herpes simplex virus type 2 (HSV-2) continues to be a common infection, affecting approximately 22% of adults ages 12 and older, representing 45 million adults in the United States alone.[4] While HSV-1 often affects the perioral region and can be known to cause genital lesions, HSV-2 is more commonly the consideration when patients present with genital lesions. Despite this, most outbreaks of the infection will present with nonspecific symptoms such as genital itching, irritation, and excoriations, which may cause diagnosis and treatment to be delayed.[4] As a result, further exposure to uninfected individuals may occur.

Etiology

Risk factors for acquiring HSV-2 infection revolve around direct exposure to fluids (i.e., saliva) from a seropositive individual containing viral products most often during sexual intercourse.[3] HSV-2 is mainly transmitted through sexual intercourse, attributing to its predominant rise starting at puberty.[3] Due to its low stability outside the body, HSV can only remain infectious for days on moist surfaces. Therefore modes of transmission other than sexual intercourse are often insignificant.[3] Both primary and recurrent HSV infections in pregnant women can lead to intrauterine transmission and resultant congenital HSV infection.[5]

Epidemiology

Herpes genitalis remains one of the most common sexually transmitted infections (STI).[3] While the majority of cases are due to HSV-2, rare but increasing cases have been found due to herpes simplex virus type 1 (HSV-1).[3] The primary mode of transmission of both HSV-1 and HSV-2 is via direct contact of open lesions. Sixteen percent of patients aging 14 to 49 were reported to be seropositive for HSV-2 from 2005 to 2010.[6] Antibodies to HSV-2 are often present by the time of puberty, and their presence often correlates with the degree of sexual activity of that individual. More women than men have been reported to be infected, and as expected, the prevalence increases with an increasing number of sexual partners. [7] Ethnically, non-Hispanic African Americans have greater rates of infection than non-Hispanic whites. About 85% to 90% of infections are unrecognized and remain undiagnosed.[8]

In the United States, HSV remains one of the most common causes of genital ulcers, and internationally, more than 23 million new cases are reported annually.[9] 

Pathophysiology

HSV-2 is transmitted through direct contact of sections in a seropositive individual who is actively shedding the virus. The virus preferentially affects the skin and mucous membranes with the virus invading epithelial cells on initial exposure and ultimately replicating intracellularly at that site. After the initial exposure and symptoms resolve, in 10 to 14 days, on average, the virus then lays dormant in the periaxonal sheath of the sensory nerves of either the trigeminal, cervical, lumbosacral, or autonomic ganglia. In these locations, the viral replication is often controlled by the patient's immune system and remains in a dormant state only to later reactive later in life.[9] When reactivation does occur, the virus travels through the sensory nerves until it reaches the mucocutaneous sites where replication then takes place and leads to vesicular clusters at the dermatological site of that sensory neuron.

Histopathology

Histological presentations of HSV-2 include the presence of dense lymphoid infiltrates with atypical lymphocytes.[10] Diagnosis is often made based on the clinical exam, but if the pathological analysis is performed, it is consistent with dense and deep infiltrates of lymphocytes near adnexal structures along with individual necrotic keratinocytes. When looking at the surface of cells, it is common to see epidermal ballooning and acantholysis, which leads to the classic vesiculation seen on the clinical exam.[11]

History and Physical

Genital symptoms are commonly seen in the outpatient primary care setting, despite many going without a clear diagnosis. HSV-2, in particular, may present as a primary infection with painful genital ulcers, sores, crusts, tender lymphadenopathy, and dysuria.[4] The classical features are of macular or papular skin and mucous membrane lesions progressing to vesicles and pustules that often last for up to 3 weeks. Genital lesions can be especially painful, leading to swelling of the vulva in women, burning pain, and dysuria.[12]

It is important to note that HSV-2 does not typically present with painless ulcers. Systemic symptoms can occur to include fever, headache, and malaise and are often due to concurrent viremia, which has been reported in up to 24% of patients in one study.[13]

Evaluation

 Recommended Laboratory Assessments[14][15]

• A direct swab of vesicular lesions (within 72 hours of onset) is ideal but avoid lesions that have evidence of crusting or healing. Do not clean area with topical alcohols before acquiring material
• Swab locations include: skin via unroofing vesicles with a sterile needle, urethra via sterile swab, the cervix through the vaginal speculum, urine, swabbing of the conjunctiva, and rectal swabs through proctoscopes [16]
• HSV serotyping
• HSV PCR (if direct swab not possible, PCR is the test of choice)
• Tzank smear - low sensitivity and cannot decipher between HSV serotypes

 Given symptoms can mimic acute urinary tract infection, consider urinalysis and culture.

 Given HSV is an STI, consider further STI work up to include:

• Gonorrhea/chlamydia testing (urine)
• HIV (known interaction between HSV-2 and HIV in which concurrent infection may occur faster than if HSV-2 was not present)
• RPR

Treatment / Management

Management of genital herpes centers around preventing its transmission and suppressing viral shedding through antiviral therapy and counseling regarding the risk of sexual transmission. 

Primary Treatment

Primary infections with multiple ulcerating lesions will resolve after approximately 19 days, regardless of treatment interventions.[12] Treatments typically categorize as either primary or non-primary. Primary infection is when the individual is experiencing their first outbreak (previously seronegative for HSV). Secondary (or non-primary) refers to an infection in a patient with preexisting immunity. Treatment is similar for both patient populations. 

Antiherpesviral agents include those that act as nucleoside analog-polymerase inhibitors and pyrophosphate analog–polymerase inhibitors. The mainstay of therapy remains acyclovir, which has antiviral activity against all herpesviruses and has been FDA approved for the treatment and suppression of both HSV and VZV.[17] Other treatments include penciclovir (which is more often used as a topical therapy for HSV labialis) and ganciclovir (which has suppression activity against CMV). These medications are preferentially taken up by those cells already infected with the virus and stop viral replication. [17] Treatment should be offered to all patients to prevent a prolonged duration of their symptoms, ideally immediately after the appearance of the first lesion.[1] 

• Acyclovir: available in topical, oral, and IV formulations. The oral formulation has quite a poor bioavailability, which has been improved with valacyclovir (see below). The benefits of acyclovir include its low side effect profile, which allows it to be tolerated for long periods. Suppressive treatment with acyclovir can prevent or delay up to 80% of recurrences, thus reducing shedding by greater than 90%.[18] Reported side effects include kidney toxicity and neutropenia when given at high doses.[17] Given its chronicity of use, resistance has been reported in immunocompromised patients and those who are immunocompetent taking acyclovir as suppressive therapy for genital herpes.[17]
• Primary herpes genitalis: 3 x 400 mg tablets PO daily for 7 to10 days
• Severe primary herpes genitalis: 3 x 5 mg/kg IV daily for 5 to 7 days
• Recurrent herpes genitalis (less than 5 to 6 episodes/year): 2 x 800 mg PO daily for 5 days 
• Prophylaxis: 2 x 400 mg PO daily for 6 months
• Valacyclovir is another formulation option that is attractive to patients
• Primary herpes genitalis: 2 x 500 mg tablets PO daily for 7 to 10 days
• Recurrent herpes genitalis (less than 5 to 6 episodes/year): 2 x 500mg PO daily for 3 days
• or
• 1 x 1000 mg tablet daily for 5 days 

Prophylaxis: 1 x 500 mg PO daily for 6 months

Treatments on the Horizon

Standard therapy for herpes simplex virus type 2 infections include acyclovir and valacyclovir. Medications on the horizon include brincidofovir and maribavir (both against CMV) and valomaciclovir (activity against HSV, VZV, and EBV). As patients seek alternative treatments that have a smaller side effect profile, essential oils have been a focus of interest.[19] HSV has demonstrated susceptibility to many essential oils and their constituents through both direct virucidal activity and inhibition of intracellular replication.[19] Topical peppermint oil has been studied due to its virucidal component, with antiviral activity reported at 99% after only 3 hours of exposure.[20] The stipulation of use and activity, however, was that peppermint oil was only effective against the virus before absorption into the host cell. As a result, it may be of particular benefit from a chronic suppressive treatment rather than post-infectious symptoms. Other oils that have been found to have antiviral effects against HSV include Australian tea tree oil and eucalyptus oil.[21]

Vaccinations

HSV vaccines are being studied to reduce the severity of symptoms and to help expedite visible lesion healing. Furthermore, by reducing shedding, the severity may be reduced, as has been seen with the Varicella-zoster vaccination.[2] No current vaccine is available for HSV.

Differential Diagnosis

 Infectious genital ulcerative conditions 

• • Syphilis
  • Chancroid
  • Lymphogranuloma venereum
  • Granuloma inguinale
• Non-infectious genital ulcerative conditions
  • Crohn disease
  • Behcet syndrome
  • Fixed drug eruptions
  • Psoriasis
  • Sexual trauma

 Genital HSV-2 infection is associated with an increased risk of HIV infection. As a result, be aware that testing for HIV infection may alter the treatment of HSV-2.[22]

Prognosis

There is no cure for HSV-2, early identification of symptoms, and prompt institution of pharmacotherapy can lead to early suppression of viral replication. Abstinence during known viral shedding can decrease the risk of transmission to a seronegative partner. The Herpes viruses as a family are responsible for significant neurological morbidity, and unfortunately, HSV-2 persists in the seropositive individual for a lifetime.

Complications

• Genital HSV-2 infection is known to be associated with an increased risk of HIV infection. As a result, be aware that testing for HIV infection may alter the treatment of HSV-2.[22] 

• Untreated HSV-2 can cause meningitis; however, any part of the nervous system may be affected by this virus.
• Aseptic meningitis occurs in 36% of women and 13% of men leading to the hospitalization of a percentage of inflicted persons. During the prodrome of genital herpes and herpetic eruption, as discussed above, affected individuals may experience more systemic symptoms such as headaches, neck stiffness, and low-grade fever. Such symptoms should lead to immediate lumbar puncture with an analysis of the CSF, often revealing a lymphocytic pleocytosis. While the CSF can be sent for viral culture, PCR is the recommended diagnostic modality.[8] 

• Acute retinal necrosis - presents with a unilateral or bilateral red eye(s), periorbital pain, and impaired visual acuity. Examination reveals episcleritis or scleritis and necrosis with retinal detachment. May occur with HSV-2 meningoencephalitis.[8]

Deterrence and Patient Education

•  Condom use recommended
• Abstain from sexual activity during periods of known active viral shedding (visible lesions)
• Consider prophylactic suppressive therapy if frequent sexual activity is likely to occur [23]

Pearls and Other Issues

• HSV cannot be cured, but suppressive therapy can help prevent spread to seronegative individuals.
• HSV has been associated with HIV infection, and thus patients with a new diagnosis of HSV should have full STI workups performed.

Enhancing Healthcare Team Outcomes

The primary care physician or provider will often be the first one to diagnose and treat HSV-2 infections. However, an interprofessional team approach is the optimal means to address this condition. [Level 5]

• Early identification of the classical vesicular lesions can lead to prompt treatment and potentially prevent spread to seronegative individuals
• The interprofessional healthcare team, to include the medical assistants and nursing staff, are pivotal in providing medical education to the patient on how to prevent unnecessary spread. This should be documented and communicated to the treating physician.
• Utilizing network public health officials can help dispense information as well as track STIs in the area leading to early identification in patients who may be otherwise asymptomatic.
• Pharmacists review medications, verify dosing, check for interactions, inform patients about use and potential side effects. They also may be involved in the purchase of condoms and can make patient recommendations.