80 Human Herpesviruses Jennifer R Stalkup Kimberly Yeung-Yue Mathijs Brentjens Stephen K Tyring The human herpesviruses (HHV) are categorized into three groups: alpha-, beta-, and gamma herpesvirinae (Table 80.1). Each contains a core of linear double-stranded DNA, an icosahedral capsid 100 to 110 nm in diameter, and an envelope with glycoprotein spikes on the surface. The pathogenesis of herpesvirus infection follows the sequence of primary infection, latency and reactivation (Fig. 80.1). The eight human herpesviruses are discussed at length in the content of this chapter and include the following: herpes simplex virus types 1 and 2 (HSV-1/HHV-1, HSV-2/HHV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7) and human herpesvirus 8 (HHV-8). HERPES SIMPLEX VIRUSES (HSV-1 AND HSV-2) Synonyms Herpes Herpes simplex Cold sore Fever blister Herpes febrilis Herpes labialis Herpes gladiatorum Scrum pox Herpetic whitlow Genital herpes Herpes progenitalis Key features Herpes simplex viruses produce primarily orolabial and genital infection characterized by primary and recurrent vesicular eruptions The use of both sensitive and specific serologic markers has enabled the epidemiology of HSV infection to be determined Antiviral therapy has significantly influenced both the course and spectrum of HSV disease Introduction Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) are ubiquitous pathogens that produce orolabial and genital herpes infections. Genital herpes is the most common sexually transmitted disease worldwide. Knowledge of the clinical manifestations, pathogenesis and histopathology of HSV infections has been paralleled by advances in the treatment of HSV infection with antiviral agents and the development of diagnostic markers to differentiate between the two HSV types. The use of both sensitive and specific serologic markers has enabled the epidemiology of HSV infections to be deciphered. Antiviral therapy has allowed the clinician to control both the course as well as the extent of HSV disease. Prevention of HSV infections via molecularly derived vaccines remains an important goal. UPDATE Date Added: 09 July 2003 Dr Fiona McCrimmon Update on the Herpes simplex virus A recent article published in the New England Journal of Medicine reported the use of a vaccine to try to prevent genital infections due to herpes simplexvirus (HSV). Two double-blind randomized trials utilized a HSV-2 glycoprotein subunit vaccine, which was given to subjects whose sexual partners had a history of genital HSV infections. 847 subjects, who were seronegative for both HSV-1 and HSV-2, and 1867 subjects, who were seronegative for HSV-2, underwent randomization and received injections. The primary end-point was the occurrence of genital herpes disease in all subjects in study 1 and HSV-2-seronegative female subjects in study 2. The vaccination was well tolerated and elicited both humoral and cellular responses. Overall the efficacy of the vaccine was 38% in study 1 (15 cases occurred in the vaccine group and 24 cases in the control group). The efficacy in female subjects in study 2 was 42% (9 cases occurred in the vaccine group and 16 in the control group). In both studies, further analysis showed that the vaccine was efficacious in women who were seronegative for both HSV-1 and HSV-2: efficacy in study 1 was 73% (p=0.01) and efficacy in study 2 was 74% (p=0.02). The vaccine was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at baseline or in men, regardless of their HSV serologic status. The authors concluded that the studies suggest that the glycoprotein D vaccine has efficacy against genital herpes in women who were seronegative for both HSV-1 and HSV-2 at baseline. Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, Tyring S, Aoki FY, Slaoui M, Denis M, Vandepapeliere P, Dubin G; GlaxoSmithKline Herpes Vaccine Efficacy Study Group. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med 2002 Nov 21;347(21):1652-61. History Herpetic lesions have been described since ancient times by such figures as Hippocrates, Herodotus and Galen. The word 'herpes' was first defined by Greek scholars as 'to creep or crawl' in reference to the spreading nature of the skin lesions. The association between herpetics lesions and genital infection was first recognized during the late 18th century. However, advancements in the histopathology and pathogenesis of herpes infections did not occur until the 20th century. Although Lipschitz was the first to suggest antigenic differences between the two HSV types, it was not until 1968 that Nahmias & Dowdle1 demonstrated that HSV-1 was more frequently associated with orolabial herpes and HSV-2 with genital infection. In the past two decades, critical advances in the treatment, diagnosis, pathogenesis and prevention of HSV infection have led to tremendous progress in our understanding of herpes simplex disease. Epidemiology Herpes simplex viruses have a worldwide distribution and produce primary, latent and recurrent infections. Over one-third of the world's population is thought to have the ability to transmit the virus during periods of viral shedding. In children less than 10 years of age, herpetic infections are often asymptomatic and of the HSV-1 type (80-90%). Analyses performed on a global basis have demonstrated HSV-1 antibodies in approximately 90% of individuals 20 to 40 years old. HSV-2 is the etiology of most genital herpes infections (70-90%), although recent studies have shown an increasing incidence attributed to HSV-1 (10-30%)2. Antibodies to HSV-2 are rarely found prior to adolescence due to the association of HSV-2 with sexual activity. The seroprevalence of HSV-2 in the US has increased by more than 30% in the past two decades with approximately 500 000 to 1 000 000 individuals acquiring primary genital HSV annually. The actual prevalence of genital herpes infection in the US is estimated to be between 40 to 60 million due to newer serologic methods of HSV detection. Factors associated with the transmission of genital herpes include age of greatest sexual activity (15 = 30 years), increased number of sexual partners, black or Hispanic race, lower income levels and education, female gender, and homosexuality and HIV-positivity3. Pathogenesis page 1235 page 1236 Table 80-1. The eight human herpesviruses, their classification and differential diagnoses. THE EIGHT HUMAN HERPESVIRUSES, THEIR CLASSIFICATION AND DIFFERENTIAL DIAGNOSES Human herpesvirus Classification Differential diagnosis HHerpes simplex virus (HSV-1) (HHV-1) Herpes simplex virus (HSV-2) (HHV-2) Alpha herpesvirinae Orolabial herpes: herpangina, aphthous stomatitis, Stevens- Johnson syndrome, pharyngitis (e.g. due to EBV), oral candidiasis, mucositis secondary to chemotherapy Genital herpes: trauma chancre (primary syphilis), aphthae, chancroid, granuloma inguinale Varicella zoster virus (VZV) (HHV-3) Alpha herpesvirinae Varicella: vesicular viral exanthem (ECHO, Coxsackie), PLEVA, rickettsial pox, HSV, insect bites, drug eruption, scabies, contact dermatitis, smallpox Herpes zoster: zosteriform HSV, localized contact dermatitis, phytophotodermatitis, bullous impetigo Epstein-Barr virus (HHV-4) Gamma herpesvirinae Group-A streptococcal infection, acute viral hepatitis, anti-convulsant hypersensitivity syndromes, toxoplasmosis, lymphoma, and primary CMV, HHV-6, HIV infections Cytomegalovirus (HHV-5) Beta herpesvirinae EBV-induced infectious mononucleosis, toxoplasmosis, viral hepatitis, lymphoma Human herpesvirus 6 (HHV-6) Gamma herpesvirinae Viral exanthems (measles, enterovirus infections, adenovirus, Epstein-Barr virus, rubella, parvovirus), scarlet fever, Rocky Mountain spotted fever, Kawasaki disease Human herpesvirus 7 (HHV-7) Gamma herpesvirinae Similar to HHV-6 Human herpesvirus 8 (HHV-8) Gamma herpesvirinae Acroangiodermatitis (pseudo-KS), bacillary angiomatosis, ecchymosis, hemangioma, angiosarcoma, pyogenic granuloma, psuedolymphoma/lymphoma Add to lightbox     Figure 80.1 Basic pathogenesis of human herpesvirus infections. Transmission of HSV can occur during both asymptomatic and symptomatic periods of viral shedding. HSV-1 is spread primarily through direct contact with contaminated saliva or other infected secretions. HSV-2 is spread primarily by sexual contact. Virus will replicate at the site of infection (i.e. the mucocutaneous surface), travel by retrograde axonal flow to the dorsal root ganglia, and establish latency until reactivation (Fig. 80.1). Latency enables the virus to exist in a relatively non-infectious state for varying durations in its host4. The virus can later be reactivated either spontaneously or by an appropriate stimulus such as stress, ultraviolet light, fever, tissue damage or immunosuppression. Typically, reactivation will produce vesicular lesions localized to the skin; however, widespread internal organ involvement can occur if viral replication is not confined to the mucocutaneous surfaces. 'Primary infection' denotes initial HSV infection in individuals without pre-existing antibodies to HSV-1 or HSV-2. 'Recurrent infection' describes the reactivation of HSV after the establishment of latency. 'Non-primary initial infection' refers to an infection with one HSV type in an individual who already has pre-existing antibodies to the other HSV type. Clinical Features Add to lightbox     Figure 80.2 Primary herpes simplex virus type 2 infection in a teenager. Note the scalloped borders. Courtesy of Jean Bolognia, M.D. HSV infections present with great variability, and asymptomatic infection is the rule rather than the exception. In primary infections, symptoms will typically occur within 3 to 7 days after exposure. A prodrome of tender lymphadenopathy, malaise, anorexia and fever as well as localized pain, tenderness and burning often occurs before the onset of lesions. Lesions are characterized by the initial development of painful, sometimes umbilicated, vesicles on an erythematous base followed by progression to pustules and/or ulcerations. Multiple and scattered vesicles typically develop. Crusting of lesions and resolution of symptoms occur within 2 to 6 weeks. A similar prodrome can precede recurrent lesions but the latter are often decreased in number, severity, and duration than those of primary infection. page 1236 page 1237 Add to lightbox     Figure 80.3 Herpes labialis with grouped vesicopustules. Add to lightbox     Figure 80.4 Recurrent herpes simplex virus type 1 infection on the cheek. Occasionally, such lesions are misdiagnosed as cellulitis. Courtesy of Kalman Watsky, M.D. The mouth and lips are most commonly involved in orolabial herpes infection with lesions also affecting the buccal mucosa, oropharyngeal membranes, and gingivae (Fig. 80.2). Primary infection often presents as a gingivostomatitis in children and is associated with a pharyngitis and mononucleosis-like syndrome in young adults. Significant edema, pain and ulceration of the oropharyngeal membranes can cause dysphagia and drooling5. Recurrent lesions appear most often on the vermillion border of the lip (Fig. 80.3). Less common sites are the perioral skin, nasal mucosa and the cheek (Fig. 80.4). In immunocompromised hosts, recurrent herpes infections can involve intraoral soft mucosa (i.e. mucosa that does not overly bone). Primary genital herpes infection produces a severe clinical picture and presents as an excruciatingly painful, erosive balanitis, vulvitis or vaginitis. In women, lesions can also involve the cervix, buttocks and perineum and are associated with inguinal adenopathy and dysuria (Fig. 80.5). Genital lesions in men typically occur on the glans penis or penile shaft (Fig. 80.6). Systemic complaints and complications are more common in women. Extragenital lesions, urinary retention and aseptic meningitis occur in 20%, 10-15% and 10% of affected women, respectively6. Aseptic meningitis is a rare complication of primary genital herpes infection in men. The presence of more extensive local involvement, regional lymphadenopathy and fever generally distinguishes primary herpes infection from recurrent disease. Add to lightbox     Figure 80.5 Primary genital herpes. In addition to hemorrhagic crusts, there are perifollicular vesicopustules. Add to lightbox     Figure 80.6 Primary genital herpes. Recurrent genital infections can be subclinical or limited in severity. Usually three to five vesicles will reappear on the genitalia with resolution within one week. Complications are uncommon. The frequency of recurrences correlates directly with the severity of the primary infection. The time course between recurrences varies greatly with individuals having an average of four to seven outbreaks annually. Surprisingly, the majority of affected individuals report no history of genital herpes infection. Symptomatic infection is eventually diagnosed in 50% of HSV-2 seropositive patients without a reported history of genital herpes7. Other HSV Infections HSV infection can occur anywhere on the body. More commonly seen in infants and children with atopic dermatitis, eczema herpeticum, also known as Kaposi's varicelliform eruption, is a more widely disseminated eruption of HSV (Fig. 80.7). In addition to atopic dermatitis, but also with burns, pemphigus, mycosis fungoides, ichthyosis vulgaris, keratosis follicularis (Darier's disease) and Sézary's syndrome8. A clue to the diagnosis is the presence of monotonous discrete 2-3 mm hemorrhagic crusts. Herpetic whitlow is herpes simplex infection of the digits and commonly affects children and dental and medical personnel who do not routinely use gloves. It can also be acquired via digital/genital contact (Fig. 80.8). Herpes gladiatorum occurs in contact sports such as wrestling and produces a disseminated cutaneous infection after the athlete comes into direct contact with infected lesions. Additional cutaneous manifestations of recurrent HSV infection include erythema multiforme and HSV folliculitis. page 1237 page 1238 Add to lightbox     Figure 80.7 Eczema herpeticum in a child with atopic dermatitis. Photograph courtesy of Harvey Blank, M.D. Add to lightbox     Figure 80.8 Herpetic whitlow due to HSV-2. HSV infection of the eye is the second most common cause of corneal blindness in the US, and typically involves infection with HSV-1 if occurring beyond the newborn period. Primary infection presents as a unilateral or bilateral keratoconjunctivitis with significant eyelid edema, tearing, photophobia, chemosis and preauricular lymphadenopathy. Branching dendritic lesions are pathognomonic findings. Recurrent episodes with unilateral involvement are common. Complications include corneal ulceration and scarring, globe rupture and blindness. Herpes encephalitis is the most common cause of sporadic, fatal encephalitis in the US. Fever, altered mental status, bizarre behavior and localized neurologic findings are common manifestations of HSV encephalitis. The temporal lobe is often involved. Mortality in untreated patients is greater than 70%, and residual neurologic defects are common9. Severe and/or chronic HSV infections are seen in immunocompromised persons including bone marrow and solid organ transplant recipients, those with lymphoma and leukemia and individuals with HIV injection. Although the most common presentation is chronic enlarging ulcerations (Fig. 80.9A, B), lesions can occur at multiple sites in addition to cutaneous dissemination. Cutaneous manifestations are often atypical. Lesions can be verrucous, exophytic, pustular or ulcerative in nature (Fig. 80.9C). Involvement of the respiratory tract, esophagus and gastrointestinal tract can occur in addition to dissemination. Neonatal herpes occurs in approximately 1 in 2000 to 5000 deliveries (Fig. 80.10). Its incidence is on the rise in association with the reported increase in the incidence of genital herpes. The risk of transmission to the neonate from an infected mother appears to be highest (33-50%) among women with first-episode genital herpes near the time of delivery and is low (<3%) among women with recurrent herpes10. Neonatal herpes has significant associated morbidity and mortality. Affected infants may have localized or disseminated cutaneous lesions as well as ocular, CNS, and multiorgan involvement. Vesicles are initially 1-2 mm in diameter and can progress to bullous lesions larger than 1 cm in diameter. Ocular involvement often presents as keratoconjunctivitis or chorioretinitis. Infants with the worst prognosis are those with disseminated disease, primarily with liver and adrenal involvement. Encephalitis is a common component of disseminated infection and manifests as seizures, lethargy, irritability, tremors, poor feeding, temperature instability, a bulging fontanelle and pyramidal tract signs. Diagnosis and Pathology Multiple laboratory tests are available to diagnose HSV infection, including viral culture, direct immunofluorescence, molecular techniques and serology. The Western blot is both 99% sensitive and specific for HSV antibodies and is the gold standard of serological diagnosis. Convenient, reliable serologic tests are available to distinguish between HSV-1 and HSV-2 antibodies. Four type-specific serologic assays based on type-specific glycoproteins gG-1 from HSV-1 and gG-2 from HSV-2 are currently approved by the FDA and are both rapid and inexpensive. The sensitivity and specificity of each of these tests varies depending on the test and the setting11. Evaluation of patients with suspected HSV encephalitis includes CSF examination, EEG and imaging studies. Polymerase chain reaction (PCR) is the preferred diagnostic method for identification of HSV DNA in cerebrospinal fluid, and is increasingly available for detection of HSV DNA from other sources. page 1238 page 1239 Add to lightbox Add to lightbox Add to lightbox     Figure 80.9 Herpes simplex virus infections in immunocompromised hosts. Enlarging ulcerations in a child with acute lymphocytic leukemia who was presumed to have a Rhizopus infection (A) and a young man with AIDS (B). Coalescence of lesions into a yellow-white plaque on the tongue (C). Add to lightbox     Figure 80.10 Neonatal herpes due to HSV-2. Widespread erosions and ulcerations are seen. Scraping of early lesions for Tzanck smears reveals multinucleated epithelial giant cells from the majority of herpetic lesions (75%). On histopathologic specimens, ballooning of the cytoplasm of keratinocytes is one of the earliest changes in the epidermis. The nuclei show degeneration and margination of chromatin to form intranuclear inclusion bodies. Multinucleated giant cells form by fusion of the infected keratinocytes. Spongiosis occurs in the epidermis, and intraepidermal vesicles appear as fluid containing large quantities of virus accumulates within the epidermis and dermis. A variably dense inflammatory response of lymphocytes, neutrophils and eosinophils infiltrates the dermis. Vascular changes may include areas of hemorrhagic necrosis and perivascular cuffing. Disseminated cutaneous disease demonstrates extensive necrosis of the epidermis with involvement of adnexal structures. In recurrent disease, the intensity of the inflammatory infiltrate in the dermis is less pronounced. Differential Diagnoses UPDATE Date Added: 09 July 2003 Dr Fiona McCrimmon Update on the Herpes Simplex Virus An article recently published in the New England Journal of Medicine reported the use of a vaccine to try to prevent genital infections due to herpes simplex virus (HSV). Two double-blind randomized trials used a HSV-2 glycoprotein subunit vaccine, which was given to subjects whose sexual partners had a history of genital HSV infections. 847 subjects who were seronegative for both HSV-1 and HSV-2 and 1867 subjects who were seronegative for HSV-2 underwent randomization and received injections. The primary end-point was the occurrence of genital herpes disease in all subjects in study 1 and HSV-2-seronegative female subjects in study 2. The vaccination was well tolerated and elicited both humoral and cellular responses. Overall, the efficacy of the vaccine was 38% in study 1 (15 cases occurred in the vaccine group and 24 cases in the control group). The efficacy among female subjects in study 2 was 42% (9 cases occurred in the vaccine group and 16 in the control group). In both studies, further analysis showed that the vaccine was efficacious in women who were seronegative for both HSV-1 and HSV-2; efficacy in study 1 was 73% (p = 0.01) and efficacy in study 2 was 74% (p = 0.02). The vaccine was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at baseline or in men, regardless of their HSV serologic status. The authors concluded that the studies suggest that the glycoprotein D vaccine has efficacy against genital herpes in women who were seronegative for both HSV-1 and HSV-2 at baseline. Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, Tyring S, Aoki FY, Slaoui M, Denis M, Vandepapeliere P, Dubin G; GlaxoSmithKline Herpes Vaccine Efficacy Study Group. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med 2002 Nov 21;347(21):1652-61. Orolabial herpes can sometimes be confused with herpangina, aphthous stomatitis, Stevens-Johnson syndrome, pharyngitis (e.g. due to EBV), oral candidiasis, and in patients receiving chemotherapy, drug-induced mucositis (Table 80.1). In herpangina, the posterior pharynx is more commonly involved, unlike HSV infection which affects the anterior portion of the mouth. Oral aphthae typically present as a single lesion on the buccal mucosa without associated vesicles. Erythema multiforme can occur secondary to HSV and Stevens-Johnson syndrome can be difficult to distinguish from HSV when only mild mucosal disease is present. Genital aphthae can be difficult to distinguish from herpetic lesions without viral culture or PCR. Exudative tonsillitis, diffuse hyperemia of the oropharynx, and petechiae of the hard and soft palate are common manifestations of EBV-induced mononucleosis. A white, curd-like coating of the tongue, buccal mucosa and pharynx is characteristic of oral candidiasis. However, in immunocompromised hosts, the possibility of co-existing infections must be considered. Trauma, syphilitic chancre, chancroid and granuloma inguinale are included in the differential diagnosis of genital herpes. The syphilitic chancre usually presents as a single lesion that is neither painful nor recurrent. The chancroid of Haemophilus ducreyi manifests as a group of tender ulcers with a yellowish-gray exudate overlying a base of granulation tissue. Granuloma inguinale and LGV are both painful, ulcerative conditions which are followed by tender inguinal lymphadenopathy. Treatment and Prevention page 1239 page 1240 Table 80-2. Antiviral therapy for herpes simplex virus and varicella zoster virus. ANTIVIRAL THERAPY FOR HERPES SIMPLEX VIRUS AND VARICELLA ZOSTER VIRUS Disease context Drug and dosage Herpes simplex infections Orolabial herpes (recurrence) Penciclovir: 1% cream applied q2 hours × 4 days Valacyclovir: 2 g PO bid × 1 day Genital herpes (first episode) Acyclovir: 200 mg PO 5x/d × 10 days or 400 mg PO tid × 10 days Famciclovir: 250 mg PO tid ×10 days Valacyclovir: 1 g PO bid × 10 days Genital herpes (recurrence) Acyclovir: 200 mg PO 5x/d × 5 days or 400 mg PO tid × 5 days Famciclovir: 125 mg PO bid × 5 days Valacyclovir: 500 mg PO bid × 3-5 days Chronic suppression Acyclovir: 400 mg PO bid Famciclovir: 250 mg PO bid Valacyclovir: 500 mg PO qd for <10 outbreaks/yr or 1 g PO qd for 10 or more outbreaks/yr Neonatal Acyclovir: 10 mg/kg IV q8 hours × 10-21 days Immunocompromised Acyclovir: 400 mg PO 5x/d × 7-14 days or 5 mg/kg IV q8 hours × 7-14 days Famciclovir: 500 mg PO bid Acyclovir-resistant HSV in immunocompromised patients Foscarnet: 40 mg/kg IV q8-12 hours × 2-3 weeks (or until all lesions are healed) Cidofovir: 1% cream qd × 2-3 weeks Varicella zoster virus infections Varicella Acyclovir: 20 mg/kg (800 mg max) PO qid × 5 days Zoster Acyclovir: 800 mg PO 5x/d × 7-10 days Famciclovir: 500 mg PO tid × 7 days Valacyclovir: 1 g PO tid × 7 days Adult immunocompromised Acyclovir: 10 mg/kg (500 mg/m2) IV q8 hours × 7-10 days Pediatric immunocompromised Acyclovir: 10 mg/kg (500 mg/m2) IV q8 hours × 7-10 days     Famciclovir is used to treat herpes labialis (using doses at or above those used for genital herpes) and famciclovir and valacyclovir are used to treat primary varicella (at doses used for shingles); valacyclovir is used to treat herpes simplex infections in immunocompromised persons (using doses at or above those used for genital herpes in immunocompetent persons) although these drugs are not specifically FDA approved for these indications. FDA-approved antiviral agents for episodic treatment of orolabial herpes in immunocompetent persons include oral valacyclovir 2 g bid for 1 day and topical 1% penciclovir (Denavir®)(Table 80.2), which results in decreased duration of the lesion, viral shedding and pain. Topical acyclovir 5% ointment is approved for limited mucocutaneous HSV infections in immunocompromised individuals. Oral famciclovir, although not approved by the FDA for herpes labialis therapy, has been shown to speed healing of herpes labialis. Both valacyclovir and famciclovir have been demonstrated to reduce postsurgical orofacial herpes outbreaks after laser resurfacing12,13. Worldwide, these oral agents are commonly used to treat episodic recurrent oro-labial herpes or as prophylaxis. For the treatment of primary and recurrent genital herpes, oral antivirals are the agents of choice. With early initiation, acyclovir, famciclovir and valacyclovir reduce the duration of viral shedding, pain and time to healing for first episode and recurrent genital herpes. Intravenous acyclovir is indicated for neonatal HSV infection, severe infections in immunocompromised hosts, and patients with systemic complications. In immunocompromised patients, it is important to treat with oral or intravenous antivirals until the cutaneous lesions are completely healed. Chronic suppressive therapy with the above oral antiviral agents is usually reserved for those with greater than six outbreaks per year, although clinicians often exercise more lenient criteria for initiation. Asymptomatic viral shedding is reduced by 95% with suppressive therapy which results in a reduction of transmission of genital herpes to a susceptible partner. In addition, daily antiviral prophylaxis may result in a complete absence of outbreaks in many persons14. Resiquimod, a topically active immune response modifier, is currently being investigated for the treatment of recurrent genital herpes and has been demonstrated to delay lesion recurrence by enhancing cellular immunity via the induction of cytokines interferon-α and interleukin-2. A phase II study with the 0.01% gel demonstrated a delay in time to the first recurrence of herpetic lesions as well as a decrease in the total number of recurrences15. The emergence of acyclovir-resistant HSV is an increasing concern for immunocompromised individuals. Foscarnet is the only antiviral drug approved by the FDA for treatment of acyclovir-resistant HSV. The role of foscarnet in HSV treatment is limited by its potent side effects and need for intravenous administration. Cidofovir is another antiviral agent which has shown efficacy in the treatment of acyclovir-resistant HSV. Although not FDA-approved, topical cidofovir has been advocated by the CDC as a 'user friendly' alternative to foscarnet16. Individuals coinfected with HIV and HSV have more severe outbreaks and more frequent viral shedding than those without HIV infection. When added to the medical regimen of HIV-infected patients, acyclovir appears to increase survival as well as to indirectly lower the HIV viral load. Investigation of the routine administration of acyclovir with HIV-specific medications in individuals coinfected with HIV and HSV is underway17. FDA approval for oral famciclovir (500 mg three times daily for 7 days) for genital and oro-labial HSV has been obtained in the US; the latter was for HIV-infected patients. page 1240 page 1241 Significant attention has been paid to the prevention of HSV disease. Between 70 and 80% of HSV is transmitted unknowingly to others during periods of asymptomatic viral shedding. Sexual abstinence is the only method for absolute prevention of genital herpes. In addition to initiating antiviral therapy, patient education regarding pathogenesis, transmission, recurrence and prevention of genital herpes is essential. Condoms are effective only if they cover all of the lesions, and are more effective at protecting susceptible females from HSV transmission than susceptible males. There is currently no licensed vaccine available for HSV, although several vaccines are under development and evaluation for both prevention and treatment of HSV infection. Large phase III trials are being conducted with a subunit HSV vaccine as well as phase I and II trials with a replication-impaired virus and a DNA-based vaccine. Other vaccines under investigation include a vectored vaccine and a genetically attenuated, live vaccine18.