Dermatology

Herpes Simplex Virus Type 1 (HSV1, fever blisters, cold sores); Herpes Simplex Virus Type 2 (HSV2, genital herpes, herpes)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients infected with Herpes Simplex Virus type 1 (HSV-1) and Herpes Simplex Virus type 2 (HSV-2) can present in many different ways. Furthermore, many patients are asymptomatic during primary and recurrent infections. Common symptoms during primary infection include a prodrome of fever, tender lymphadenopathy, anorexia, headache, sore throat, and malaise in addition to localized paresthesia, pain, edema, tenderness, and burning.

These symptoms, which usually develop within 3 to 7 days after viral exposure, are usually followed by the development of painful, grouped vesicles on an erythematous base. The vesicles may umbilicate and then further evolve into pustules and/or shallow ulcerations with a characteristic scalloped border. The lesions then crust over and symptoms resolve within 2 to 4 weeks. Recurrent infections are less severe than the primary infection and are characterized by symptoms that are usually decreased in duration, severity, and number.

Clinicians should also be aware of some discerning characteristics in the patient's history that can help distinguish HSV-1 from HSV-2 infections. These characteristics include age of patient, area of involvement, history of sexual activity, history of immunosuppression, and history of sexually transmitted disease (STD).

Characteristic findings on physical examination

Multiple scattered or coalescing vesicles, sometimes umbilicating, on an erythamatous base are classic HSV lesions seen on physical examination. The vesicles progress to pustules and/or shallow ulcerations that ultimately crust and resolve. It is important to note that the underlying erythema can persist after the lesions have disappeared. During primary infection, tender lymphadenopathy, malaise, fever, and edema can also be seen.

HSV-1 lesions are most often found on lips, mouth, philtrum, buccal mucosa, gingivae, and oropharyngeal membranes. HSV-1 is also an increasing cause of genital herpes disease. Other less common locations for HSV-1 lesions include finger tips, eye (branching dendritic lesions), and cheeks. Patients with primary HSV-1 infection can also present with signs of pharyngitis, gingivostomatitis, significant pharyngeal edema leading to dysphagia and drooling, keratoconjunctivitis (if eye is involved), and a mononucleosis-like syndrome. The mouth and lips are the most common anatomic locations with lesions typically presenting on the buccal mucosa and gingivae. Recurrent HSV-1 lesions usually appear on the vermillion border of the lip.

HSV-2 lesions are most commonly found on the penis (foreskin, glans, shaft, and base), labia, vagina, and buttocks. Women may also develop lesions on the cervix and/or perineum. Patients with primary HSV-2 infection will frequently present with inguinal adenopathy and painful, erosive balanitis, cervicitis, or vaginitis (Figure 1). Recurrent HSV-2 lesions appear at the initial site of infection, but are usually decreased in number, severity, and duration.

Figure 1.

Characteristic skin lesions on adult with primary HSV-2. (Courtesy of Dr. Gary White.).

Expected results of diagnostic studies

Thorough history and physical examination are usually sufficient to properly diagnose HSV-1 and HSV-2 infections. Additional testing to confirm the diagnosis is available, but not always necessary. However, the diagnosis is particularly important in genital herpes and is recommended to confirm the diagnosis. Testing is also recommended in atypical presentations of genital herpes, extra-genital complications, and to rule out other ulcerative genital dermatoses. Because HSV-1 has become a frequent etiology of genital herpes, causing up to 50% of first episode cases in developed countries, differentiation between HSV-1 and HSV-2 holds important prognostic information for the patient including risks for recurrence. Direct detection of the virus in symptomatic patients can be done with swabs from active mucocutaneous genital lesions and from previously involved mucocutaneous sites in patients with asymptomatic infection. In active lesions, collection of vesicular fluid or exudate from the base of vesicles is the method of choice. Available tests include antigen detection by direct immunoflorescence, nucleic acid amplification tests (NAATs) for viral DNA detection, and viral culture and typing. NAATs, among them real-time PCR, is currently one of the most sensitive and specific tests available and is considered a "preferred" test by the CDC. Real time PCR offers clinicians accurate results with the added benefit of viral typing and quantification of viral load. Another important advantage of molecular methods is the possibility of detection of asymptomatic HSV shedding, although a negative test does not exclude the diagnosis due to intermittent viral shedding.

Antigen detection using direct immunofluorescence assay (DIF) is rapid but has lower sensitivity compared to PCR, and is only useful in patients with fresh lesions. Viral culture has classically been the gold standard for diagnosing genital herpes and is highly specific, but it has lower sensitivity than PCR and inappropriate sample handling can limit sensitivity further. Additionally, the sensitivity for viral culture is lower in older or crusted lesions, and in recurrent outbreaks and thus culture is most successful with fresh lesions in primary HSV outbreaks. Type specific antibody tests, including the gold standard Western blot analysis, are also available which can differentiate between HSV-1 and HSV-2 based on detection of glycoprotein G-1 in HSV-1 and glycoprotein G-2 in HSV-2. These methods can be useful in identifying asymptomatic carriers, in patients where other tests have been nondiagnostic, and in patients with recurrent or atypical presentations. Serology is not routinely used in clinical practice but can be useful to determine whether partners of persons with clinical herpes lesions are at risk. The mean time to seroconversion where antibodies will become detectable is 3-4 weeks following initial infection.

Tzanck smears are rapid and inexpensive, and can be used to identify multinucleated giant cells and confirm a diagnosis of herpes simplex or herpes zoster infection but cannot differentiate between the two.

Diagnosis confirmation

The differential diagnosis of HSV-1 includes aphthous stomatitis, herpangina, oral candidiasis, and Stevens-Johnson syndrome. Aphthous stomatitis presents as tender shallow ulcers on the inner lip, buccal mucosa, or upper throat. Distinguishing these ulcers from herpetic lesions is often difficult without further diagnostic HSV testing. However, aphthous stomatitis never presents with vesicles and is never preceded by a viral prodrome. Unlike HSV, which recurs at the site of primary infection, recurrent aphthous ulcers typically develop in different areas of the mouth.

Herpangina is a viral illness, usually caused by Coxsackie group A viruses, that presents with multiple shallow ulcers and blisters on the inside of the mouth. It also commonly presents with a variety of symptoms that include fever, sore throat, headache, anorexia, and dysphagia. Unlike HSV, which is recurrent and found mostly on the anterior portion of the mouth, herpangina rarely recurs and almost always affects the posterior pharynx.

Oral candidiasis, or thrush, is an infection caused by yeast that is typically found on the mucous membranes of the mouth. It is usually easy to differentiate the two on physical examination based on the thick white plaques on the tongue, pharynx, and buccal mucosa that are typical of oral candidiasis. However, in an immunocompromised patient, these two disease entities can often co-exist and present with similar physical examination findings. Mild forms of Stevens-Johnson syndrome can sometimes present similarly to primary HSV infection, but unlike HSV, it is usually associated with medication use.

The differential diagnosis of HSV-2 includes primary syphilis, chancroid, Behçet's syndrome, drug eruptions, and contact dermatitis. Primary syphilis, the "great imitator", is transmitted sexually and presents as a painless ulceration (chancre) that can form anywhere on the genitalia, lips, etc. It, too, can be difficult to distinguish from herpetic lesions without further testing. However, unlike herpetic lesions, chancres are not recurrent or painful. Furthermore, they almost always present as a single lesion.

Chancroid is a sexually transmitted bacterial infection, caused by Haemophilus ducreyi, that presents on the genitalia as multiple tender sores and ulcerations. Unlike HSV, chancroid is characterized as nonrecurring, deep-seated, painful ulcers with a base that is covered with yellowish-gray exudate. In addition, herpetic lesions never present with suppurative adenopathy, which is a pathognomonic finding of chancroid. Contact dermatitis can also present similarly to HSV, but unlike herpetic lesions, it occurs following exposure to a substance in the affected area.

Recurrent ulcer would support a diagnosis of HSV however, if diagnostic testing does not support this diagnosis, then non-infectious etiologies such as Behçet's disease or fixed drug eruption should be considered. Proper history taking including recent use of any medications and systemic symptoms can help differentiate between these two.

Who is at Risk for Developing this Disease?

Herpes simplex viruses are ubiquitous and prevalent worldwide. It is estimated that one third to one half of the world's population has the ability to transmit the virus through viral shedding. Approximately 80-90% of people worldwide have antibodies against HSV-1 with seroprevalence being about 58% in the United States. HSV-1 accounts for the majority of non-genital HSV-induced infections in humans, and is an increasing cause of genital infections. The majority of primary HSV-1 infections occur during childhood and up to 80% of cases are asymptomatic. The incidence of infection is higher in younger patients and those of lower socioeconomic status. In fact, in lower socioeconomic populations in the United States, HSV-1 affects nearly 33% by the age of 5 and 70-80% by late puberty. Recurrent HSV-1 infection is common and occurs in 33% of infected patients.

Approximately 16% of the US population or 60 million Americans are infected with HSV-2. In the United States the disease disproportionately affects African-Americans, with a seroprevalence of 39.2% compared to 12.3% in non-Hispanic whites. with 39.2 According to CDC estimates, 776,000 annually in the United States get new genital herpes infections. Although worldwide, HSV-2 accounts for the majority of genital herpes infections, a recent large prospective study demonstrated that the rate of primary HSV-1 infection was over twice that of HSV-2 and presented most commonly as genital rather than oral disease. Recent data also indicates that the majority of primary infections (74% of HSV-1; 63% of HSV-2) are asymptomatic. Another important characteristic to remember is that genital herpes infections caused by HSV-2 tend to be more severe than those caused by HSV-1, are more likely to have recurrent episodes (median 4 recurrences per year vs 1.3 per year in HSV-1), and have a greater frequency of subclinical viral shedding. Unlike HSV-1, HSV-2 is usually transmitted through sexual contact and therefore rarely found in children. Risk factors for HSV-2 infection include an increased number of sexual partners, female gender, Hispanic or black race, low socioeconomic status, and co-infection with other STDs. There is also a greater incidence of HSV-2 infection in patients between 15 and 30 years old.

What is the Cause of the Disease?

HSV-1 and HSV-2 infections are named after the respective viruses. These infectious organisms are commonly known for the primary and recurrent orolabial and genital vesicular eruptions that they produce. Transmission of the virus, which can occur during both asymptomatic and symptomatic periods, depends on direct contact between a host that is actively shedding the virus and a vulnerable seronegative individual. Recent research has shown that infected individuals exhibit frequent, brief shedding episodes that are typically asymptomatic. These episodes are much more frequent than previously thought and data now indicates that most HSV transmission occurs in asymptomatic patients. In fact, recent studies have shown that asymptomatic shedding occurs in the genital tract of 80-90% of HSV-2 seropositive individuals on approximately 20% of days, which means the majority of transmission of genital herpes occurs in asymptomatic individuals.

Transmission of the HSV-1 virus occurs primarily through direct contact with infected mucosal secretions, such as saliva, or by the sharing of eating/grooming utensils. The HSV-1 virus is usually acquired during infancy or childhood and is most commonly associated with orolabial infection or herpes labialis. The HSV-2 virus, on the other hand, is most commonly associated with genital herpes and is spread primarily by sexual contact with an infected person. Once the HSV-1 or HSV-2 virus comes in contact with abraded or damaged skin or a mucosal surface, it will replicate at the site of primary infection and eventually travel via retrograde axonal transport to the dorsal root ganglia where it will become latent and avoid the host's immune system. This latent period, which varies among hosts, is where the virus will remain until it is reactivated.

When the virus is reactivated, either spontaneously or via a provocative trigger such as UV light, stress, trauma, fever, menstruation, tissue damage, or immunosuppression, it will travel to the area of skin that corresponds to the sensory root ganglia where it resides and manifests itself in the form of clear vesicles or mucosal ulcerations (Figure 2).

Figure 2.

Characteristic skin lesion on adult with recurrent HSV-2. (Courtesy of Dr. Stephen Tyring.).

Systemic Implications and Complications

Some systemic cutaneous complications of HSV include eczema herpeticum, herpetic whitlow, herpes gladiatorum, aseptic meningitis, herpes encephalitis, and erythema multiforme. Eczema herpeticum, which is also known as Kaposi varicelliform eruption, is a life-threatening disseminated herpetic infection that occurs in patients with preexisting dermatoses, such as atopic dermatitis (most common), burns, or pemphigus. It usually appears as small, uniform, distinct hemorrhagic crusts in either a dermatomal or widespread distribution.

Herpetic whitlow is HSV infection of the hand (Figure 3) that is accompanied by secondary lymphadenitis. It used to be common in dental and medical personnel who treat HSV patients, but now is much more commonly seen in young adults that touch HSV-infected genitals. Herpes gladiatorum is a disseminated HSV infection transmitted by skin-to-skin contact that is strongly associated with contact sports such as wrestling, rugby, or football.

Figure 3.

Characteristic skin lesion on adult with herpetic whitlow. (Courtesy of Dr. Gary White.).

Erythema multiforme is a cutaneous disorder that can occur following medication use or infection, although recurrent cutaneous HSV infections remain the most common predisposing factor. It classically presents as pruritic, symmetrically distributed "target" lesions initially presenting on the extremities that resolve in 7 to 10 days.

Keratoconjunctivitis is a common complication of HSV-1 infections occurring beyond the newborn period. It is a leading cause of corneal blindness in the United States second only to trauma. Presenting unilaterally or bilaterally, it can cause significant photophobia, chemosis, periocular edema, lymphadenopathy, tearing, and branching dendritic lesions (pathognomonic finding). Without proper treatment, herpetic infections of the eye can lead to corneal scarring or ulceration, orbital rupture, and blindness.

One of the most severe complications of HSV infection is herpetic encephalitis (HSE). In fact, it is the most common cause of sporadic, fatal encephalitis in the United States. HSE commonly affects the temporal lobes and can cause a variety of signs including altered mental status, behavioral changes, fever, cerebral edema, and seizures. Without proper treatment, HSE is fatal in approximately 70% of patients. Even with proper treatment, it can cause significant irreversible damage with only 2.5% of patients achieving full neurologic recovery. Due to its poor prognosis, it should always remain high on the differential of any patient presenting with focal neurologic findings and deteriorating or altered mental status.

Neonatal herpes is another particularly devastating complication that occurs in 1 of every 3500 deliveries. The risk of vertical transmission from mother to child is significantly higher in mothers with primary HSV infection (33%) versus mothers with recurrent HSV infection (3%). Neonatal herpes has an extremely poor prognosis that depends directly on the amount of systemic involvement. Neonatal severity ranges from localized cutaneous, oral, and/or ocular involvement to disseminated infection affecting multiple organs and organ systems including the CNS, GI tract, liver, adrenals, etc.

Complications of neonatal herpes include keratoconjunctivitis, chorioretinitis, adrenal failure, liver failure, encephalitis, disseminated skin involvement, and death (80% of untreated patients).

Treatment Options

The therapeutic options, guidelines, and indications for treatment are identical in patients with HSV-1 or HSV-2 infection. Although there has been some promising work on therapeutic and prophylactic vaccines, to date there remains no FDA-approved vaccine for genital herpes. Because there is no cure for genital herpes, therapy is aimed at controlling the signs and symptoms of an outbreak. Studies have consistently shown that antiviral treatment and supportive therapy can effectively decrease the severity, duration, frequency, and spread of HSV infections. As in any infection, treating HSV at the first sign of an outbreak is crucial and should never be delayed.

Oral antivirals

Acyclovir (ACV), valacyclovir (VACV), and famciclovir (FCV) remain the mainstay of HSV-1 and HSV-2 treatment. VACV and FCV are also the mainstay drugs for the suppression of genital herpes. Additionally, these drugs are also ideal for those with frequent recurrences or with ocular HSV. Suppressive therapy with ACV has been shown to decrease the recurrence rate by 50%. ACV has also been shown to reduce asymptomatic viral shedding of HSV-2 by 95% and another study demonstrated that once-daily VACV resulted in a 50% decrease in HSV-2 transmission. These acyclic purine analogs block viral replication by inhibiting viral DNA polymerase. They are equivalent in their efficacy and safety and can be used to treat both primary and recurrent HSV infections. If availability and cost are not issues, FCV or VACV should be used instead of ACV because of their greater bioavailability and decreased dosing frequency, which, in turn, results in increased patient compliance.

Topical therapy

Topical acyclovir cream and ointment, penciclovir cream, and docosanol cream are topical formulations used to treat both oral and genital herpetic infections. Although preferred by many patients, due to reduced cost, over the counter availability of docosanol cream, and non-systemic nature, these drugs offer minimal benefit due to their low efficacy and inability to penetrate the stratum corneum.

The recently approved topical ACV cream mixed with 1% hydrocortisone (Xerese®) may be beneficial in preventing ulcerative lesions if used early in the course of disease. On the other hand, trifluridine ophthalmic solution and vidarabine ophthalmic ointment are two very effective topical agents used to treat HSV-induced keratoconjunctivitis.

Intravenous therapy

High-dose intravenous acyclovir is also available for the treatment of disseminated HSV infection, mucocutaneous HSV infections in immunocompromised patients, HSE, eczema herpeticum, and neonatal HSV infections.

Alternative therapy

Intravenous foscarnet, intravenous cidofovir, and topical cidofovir are alternative therapies for HSV infection in patients with disease that is resistant to acyclovir. This is especially true in immunocompromised patients with ACV-resistant HSV infections. It is important to note that ACV-resistant HSV strains are also commonly cross-resistant to VACV and FCV as well. However, foscarnet and cidofovir are more toxic than ACV, and therefore, should never be used as first-line HSV treatment.

Supportive therapy

Symptomatic relief is best achieved through prompt treatment with antiviral medications. However, medications such as topical lidocaine or benzocaine, ibuprofen, acetaminophen and narcotic analgesics are also available if further symptom relief is required.

Vaccines

The development of an effective vaccine against HSV-1 and HSV-2 has proven challenging, and no vaccine is currently available. Two studies of a prophylactic glycoprotein D2 alum/MPL vaccine demonstrated prevention of genital herpes disease in 73% (first study) and 74% (second study) of seronegative women whose regular sexual partner had a history of genital herpes. A second prophylactic vaccine (ICP10DPK, AuRx) was shown to prevent recurrent disease in 44% of immunized subjects and to reduce the frequency and severity of recurrences in subjects that were not fully protected. A more recent study of HSV-2 glycoprotein D has shown 58% efficacy against HSV-1, but was not efficacious against HSV-2.

Optimal Therapeutic Approach for this Disease

Herpes Labialis (first episode or recurrent disease)

  • Penciclovir 1% cream applied every 2 hours for 4 days

  • Docosonal 10% cream applied 5 times a day

  • Acyclovir 200 mg orally 5 times a day for 5 days or 400 mg orally 3 times a day for 5 days

  • Valacyclovir 2 grams orally twice a day x 1 day

  • Famciclovir 1500 mg orally daily x 1 day

Herpes Labialis (suppressive therapy)

  • Acyclovir 400 mg orally twice a day

  • Valacyclovir 500 mg orally daily

  • Famciclovir 250 mg orally twice a day

Herpes Genitalis (first episode)

  • Acyclovir 200 mg orally 5 times a day for 10 days or 400 mg orally 3 times a day for 10 days

  • Valacyclovir 1 gram orally twice a day for 10 days

  • Famciclovir 250 mg orally 3 times a day for 10 days

Herpes Genitalis (recurrent disease)

  • Acyclovir 200 mg orally 5 times a day for 5 days or 400 mg orally 3 times a day for 5 days

  • Valacyclovir 500 mg orally twice a day for 3 days

  • Famciclovir 125 mg orally twice a day for 5 days

Herpes Genitalis (suppressive therapy)

  • Acyclovir 400 mg orally twice a day

  • Valacyclovir 500 mg orally daily or 1 gram orally daily, if more than 9 outbreaks in previous year

  • Famciclovir 250 mg orally twice a day

Neonatal HSV

  • Acyclovir 10 mg/kg intravenously (IV) every 8 hours for 10-14 days

Mucocutaneous HSV infection in immunocompromised patients

  • Acyclovir 5 mg/kg (IV over 1 hour) every 8 hours for 7 days

Recurrent herpes labialis or genitalis in immunocompromised patients

  • Acyclovir 400 mg orally 5 times a day for 7-14 days

  • Valacyclovir 500 mg to 1 gram orally twice a day for 7 days

  • Famciclovir 500 mg orally twice a day for 7 days

Herpes labialis or genitalis in immunocompromised patients (suppressive therapy):

  • Acyclovir 400 mg orally 3 times a day

  • Valacyclovir 500 mg to 1 gram orally twice a day

  • Famciclovir 500 mg orally twice a day

Patient Management

Good patient education is the key to good patient management. Patients should know that although there is no cure or vaccine, there are ways to decrease the transmission of HSV. If the patient or his/her partner complain of any prodromal symptoms or have any signs of active infection, it is important to educate them to practice good hygiene and to keep active lesions away from other parts of their body or their partner's. If oral herpes is present, instruct the patient to refrain from kissing or sharing grooming or eating utensils. If genital herpes is present, advise the patient to avoid sexual activity of any kind.

Patients must understand that condom use and antiviral suppression can help reduce the spread of herpes, but they do not prevent it. Finally, it should be explained to patients that HSV can spread from person to person without the presence of an active sore. HSV screening with serologic testing is suggested for any patients who are evaluated in a clinical setting for sexually transmitted diseases or for those patients that are at high risk for STD/HIV infection. Screening is also recommended for HIV-positive patients and patients in partnerships or considering partnerships with HSV-infected individuals. Serologic testing is not, however, routinely recommended in pregnant females or the general population.

Unusual Clinical Scenarios to Consider in Patient Management

Other cutaneous HSV infections (herpetic whitlow and herpetic gladiatorum)

First Episode

  • Acyclovir 200 mg orally 5 times a day for 10 days or 400 mg orally 3 times a day for 10 days

  • Valacyclovir 1 gram orally twice a day for 10 days

  • Famciclovir 250 mg orally 3 times a day for 10 days

Recurrent Disease

  • Acyclovir 200 mg orally 5 times a day for 5 days or 400 mg orally 3 times a day for 5 days

  • Valacyclovir 500 mg orally twice a day for 3 days

  • Famciclovir: 125 mg orally twice a day for 5 days

Suppressive Therapy

  • Acyclovir 400 mg orally twice a day

  • Valacyclovir 500 mg orally daily

  • Famciclovir 250 mg orally twice a day

HSV keratoconjunctivitis

  • Trifluridine 1% ophthalmic solution 1 drop every 2 hours (maximum 9 drops/day)

  • Vidarabine 3% ophthalmic ointment 5 times a day at 3-hour intervals

HSV encephalitis

  • Acyclovir 10 mg/kg IV over 1 hour every 8 hours for 14 days

Acyclovir-resistant HSV (Figure 4; alternative therapy)

Figure 1067.

Acyclovir-resistant HSV-2 lesion in HIV infected patient. (Courtesy of Dr. Stephen Tyring.).

  • Foscarnet 40 mg/kg intravenously (over 1 hour) every 8-12 hours for 14-21 days

  • Cidofovir 1% cream can be compounded as alternative therapy

What is the Evidence?

Whitley, RJ, Gnann, JW, Tyring, SK, Moore, AY, Lupi, O. "Herpes simplex viruses". Mucocutaneous manifestations of viral diseases. Informa Healthcare. 2010. pp. 65-97.

(A comprehensive overview of herpes simplex viruses with a large collection of clinical images.)

Fife, KH, Barbarash, RA, Rudolph, T, Degregorio, B. "Valacyclovir versus acyclovir in the treatment of first-episode genital herpes infection: results of an international, multicenter, double-blind, randomized clinical trial". Sex Transm Dis. vol. 24. 1997. pp. 481-6.

(A study demonstrating that twice-daily valacyclovir is as effective and well tolerated in the treatment of first-episode genital herpes as 5-times-daily acyclovir.)

Corey, L, Wald, A, Patel, R, Sacks, SL. "Once-daily valacyclovir to reduce the risk of transmission of genital herpes". N Engl J Med. vol. 350. 2004. pp. 11-20.

(A study demonstrating that once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.)

Tyring, SK. "Advances in the treatment of herpesvirus infections: the role of famciclovir". Clin Ther. vol. 20. 1998. pp. 661-70.

(A review of the etiology of HSV-2 and the key studies that demonstrate the efficacy of famciclovir in the management of this condition.)

Tyring, SK, Diaz-Mitoma, F, Shafran, SD, Locke, LA. "Oral famciclovir for the suppression of recurrent genital herpes: The combined data from two randomized controlled trials". J Cutan Med Surg. vol. 7. 2003. pp. 449-54.

(A study demonstrating that famciclovir twice daily is an effective, well-tolerated treatment for the suppression of genital HSV infection in patients with frequent recurrences.)

Gupta, R, Wald, A, Krantz, E, Selke, S. "Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract". J Infect Dis. vol. 190. 2004. pp. 1374-81.

(A study demonstrating the efficacy of valacyclovir and acycolovir in suppressing the frequency and quantity of genital HSV shedding.)

Stanberry, LR, Spruance, SL, Cunningham, AL, Bernstein, DI. "GlaxoSmithKline Herpes Vaccine Efficacy Study Group. Glycoprotein-D-adjuvant vaccine to prevent genital herpes". N Engl J Med. vol. 347. 2002. pp. 1652-1661.

(A study on the efficacy of using Glycoprotein-D-adjuvant to prevent genital herpes infections.)

Aurelian, L. "Herpes simplex virus type 2 vaccines: new ground for optimism". Clin Diagn Lab Immunol. vol. 11. 2004. pp. 437-445.

(Review of herpes vaccines trials so far with promising new trial results).

Belshe, RB, Leone, PA, Bernstein, DI, Wald, A. "Herpevac Trial for Women. Efficacy results of a trial of a herpes simplex vaccine". N Engl J Med. vol. 366. 2012. pp. 34-43.

(More recent vaccine trial showing some promise in HSV-1 but no efficacy against HSV-2.)

Hofstetter, AM, Rosenthal, SL, Stanberry, LR. "Current Thinking on Genital Herpes". Current Opin Infect Dis.. vol. 27. 2014. pp. 75-83.

(Review article on genital herpes highlighting all the recent advances in understanding of transmission, asymptomatic viral shedding and epidemiological data from around the world.)

LeGoff, J, Pere, H, Belec, L. "Diagnosis of genital herpes simplex virus infection in the clinical laboratory". Virol J. vol. 12. 2015 October 13. pp. 167.

(Review article on all available laboratory techniques for the diagnosis of herpes simplex virus infections.)
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