Manual of Dermatologic Therapeutics
7th Edition
© 2007 Lippincott Williams & Wilkins
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15
Herpes Simplex
Danielle M. DeHoratius
I. Definition and Pathophysiology
Cutaneous herpes simplex infections take two distinct forms: (i) the painful and disabling primary infection of previously uninfected individuals and (ii) the common, bothersome recurrent form colloquially known as cold sores or fever blisters. These infections are asymptomatic in up to 80% of patients. The mode of transmission is by close personal contact. The virus is inoculated either through mucous membranes or through small cracks in the skin. By 4 years of age, approximately 50% of the population has antibodies to herpes simplex virus (HSV) indicative of prior exposure. This percentage increases to 60% to 70% by age 14. Following primary infection, effective immunity develops in some individuals, but 20% to 45% will have recurrent disease. Seven percent of the general population has at least two episodes of recurrent facial herpes per year.
Herpes simplex is a deoxyribonucleic acid (DNA) virus, infects humans alone, and has an almost universal distribution. There are two types of HSV: type 1, which is usually responsible for nongenital herpetic infections, and type 2, which is usually the agent involved in genital infections in both men and women. It is important to recognize that the herpesvirus has three unique properties. It has the capacity to invade and replicate within the nervous tissue. The virus then remains latent within the neural tissue, most commonly the trigeminal ganglia for HSV-1 and the sacral nerve root ganglia for HSV-2. Lastly, the latent virus has the capacity to reactivate and replicate, causing cutaneous disease. There are certain biologic differences between the two types. For example, HSV-2 genital infections recur more frequently than genital herpes due to HSV-1, whereas nongenital HSV-1 infections recur more frequently than nongenital herpes due to HSV-2. Genital HSV infections recur sixfold more frequently than oral-labial HSV infections. Previous infection with one type of HSV does not appear to provide effective immunity to subsequent infection with the other.
True primary infection occurs in a person with no previous exposure to HSV and is usually quite severe. First-episode genital infections can occur in persons who either had previous nongenital HSV infection or have serologic evidence of prior subclinical exposure to the virus. Although not sufficient to prevent reinfection, this degree of immunity at least confers partial protection such that first-episode genital infection is less severe than a true primary one. The primary infection, which has an incubation period of 3 to 12 days following exposure, runs a clinical course of 1 to 3 weeks; recurrent lesions heal more quickly (7 to 10 days). Viral excretion persists for 15 to 42 days after the primary infection. Viral titer in recurrent orofacial disease decreases dramatically by 2 days, and most lesions are negative by 5 days. In women with recurrent genital herpes, virus is present for a mean of 4.8 days, while 16% may continue to shed virus from lesions after 6 days. Asymptomatic shedding of HSV has also been demonstrated from both oropharyngeal and genital sites at low rates without evident lesions. The most recent studies suggest that most transmission of genital herpes occurs from persons who asymptomatically shed virus. The annual risk of transmission from a sexual partner with genital herpes in a heterosexual relationship is approximately 10%.
Genital herpes simplex is one of the most common sexually transmitted diseases (STDs). The prevalence of HSV-2 infection in the United States ranges from 20% to 60%. The average man in the United States has a 40% to 60% chance of having been infected with this virus. Even without considering its sometimes-significant psychosocial impact, genital herpes simplex infection may pose other health problems for female patients. Pregnant women with a history of genital herpes must be carefully monitored.
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The risk of HSV infections in neonates exposed to the virus at the time of vaginal delivery to mothers with a history of recurrent genital HSV infections is very low (≤8%). The presence and titer of neutralizing antibody to HSV contribute to this low rate. Infants born to women who have primary HSV infection are at more than 50% risk of developing a clinical infection, and a C-section is indicated in this situation. Neonatal herpes is a serious disease with up to a 50% mortality rate and a significant chance of permanent sequelae among its survivors. Perinatal HSV infection is part of the TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex) syndrome. Up to 60% to 80% of babies infected with HSV are delivered by women with no evidence of clinical HSV on examination. Disease during early pregnancy may produce malformations that are clinically indistinguishable from those produced by cytomegalovirus. In addition to the potential threat to the fetus when HSV infects the reproductive tract during pregnancy, an etiologic role in cervical dysplasia and carcinoma has been proposed, although not proved. Women with genital herpes simplex infections appear to have a five to ten times greater likelihood of developing cervical carcinoma than uninfected women, and HSV-2 antigens have also been found in a high percentage of atypical epithelial lesions of the vulva. These findings may reflect infection by a ubiquitous agent. Alternatively, an HSV infection may be a covariable. Anorectal herpes is being recognized with increased frequency. When caused by HSV-2, it is usually transmitted by anal intercourse. HSV-1 causes perianal infections in immunosuppressed patients, presumably by autoinoculation from orofacial lesions.
After primary infection, the virus appears to remain latent in sensory ganglia. In patients with recurrent herpes, the virus is periodically reactivated and conducted to the epidermis through peripheral nerve fibers. It then replicates in the skin, producing the recurrent herpetic lesion. Trigger factors include emotional stress, physical trauma (including genital trauma), sunburn, menses, fever, and systemic infections. The long-term natural history of recurrent nongenital herpes infection is not well characterized. The virus type influences the recurrence rate of genital herpes, as does gender, with men being at greater risk for recurrent disease. There is a great deal of variation in recurrence rates among individuals. Over time, most patients experience clinically significant reductions in disease severity. Rates of recurrence begin to decline by the second year after initial outbreaks (1).
Patients with atopic dermatitis risk the development of generalized lesions (eczema herpeticum), regardless of whether their eczema is active. Diseases or drugs that interfere with host response, particularly with cell-mediated immunity, also predispose to widespread, slowly healing, and more destructive infections. Those with lymphoreticular malignancies or thymic defects and immunosuppressed transplant or acquired immunodeficiency syndrome (AIDS) are most prone to severe HSV infections.
II. Subjective Data
  • Primary symptomatic oral or genital infections
    • Infections on mucosal surfaces are preceded by a day or two of local tenderness.
    • The lesions are accompanied by severe and disabling pain and tender lymphadenopathy, often making it impossible for those with gingivostomatitis to eat or drink or patients with extensive genital involvement to walk or urinate.
    • High fever and purulent malodorous secretions accompany oral and vaginal infections.
    • Primary infection in men usually results in painful penile lesions. It may also cause urethritis with dysuria and discharge.
    • Anorectal infection may be complicated by tenesmus, constipation, and urinary retention.
  • Recurrent lesions are preceded by several hours of a burning or tingling sensation in 80% of patients. They are uncomfortable, but much less than the lesions of the primary infection. Virus is present in the lesion at the time of prodromal symptoms.
III. Objective Data (See color insert)
  • Primary infection
    • Acute herpetic gingivostomatitis is the most frequent manifestation of primary infection, usually seen in young children. It is usually abrupt at onset and is
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      associated with a high fever, anorexia, and listlessness. This acute episode lasts from 5 days to 1 week.
      • Vesicles, erosions, and maceration are seen over the entire buccal mucosa; this can involve the perioral skin because of contamination.
      • Marked erythema and edema of the gingiva are typical.
      • Submandibular adenopathy is usually present and is tender.
    • Acute herpetic pharyngotonsillitis is usually seen in adults and is an oropharyngeal infection of HSV-1. Symptoms are usually a sore throat, fever, malaise, and headache. HSV-2 can be an etiologic agent; however, this usually involves an orogenital contact.
    • Vulvovaginitis is seen most frequently in girls and young women.
      • It consists of widespread vesicles, erosions, and edema in the vulva, labia, and surrounding skin.
      • These areas become very edematous, erythematous, and extremely tender.
      • A profuse vaginal discharge is present, and some women develop urinary retention.
      • Bilateral, tender, inguinal adenopathy is usually present.
    • Urethritis in men is accompanied by a watery discharge and the occasional presence of vesicles around the urethral meatus.
    • Inoculation herpes is commonly found on the paronychial area (herpetic whitlow) of nurses and physicians, particularly those involved with mouth care, and may also be found on previously traumatized or burned skin. The lesions are characterized by the sudden appearance of vesicles and are accompanied by extreme local pain, sometimes a sterile lymphangitis, and rarely a systemic reaction. The first episode may last up to 28 days. Recurrent infections most often occur in adults with HSV-2 infection. Herpetic whitlow is often misdiagnosed as a bacterial paronychia and mistreated with incision and drainage of lesions, with subsequent implantation of the virus into the incised tissue.
    • Cervicitis is often asymptomatic but nevertheless important to recognize in pregnant women because of the associated risk of fetal infection and spontaneous abortion. Pregnant women who acquire genital herpes during the first 20 weeks of pregnancy have an increased risk of abortions, whereas the infants of those who acquire an infection after 20 weeks have an increased incidence of prematurity and birth defects.
    • Anorectal herpes is characterized by the typical cutaneous lesions as well as rectal ulcerations. Extensive indolent lesions are not uncommon in patients with AIDS.
    • In the United States, genital ulcers are most commonly caused by HSV-2. These ulcers may contain multiple pathogens, and the patient should be evaluated for coexisting STDs. Most of the episodes of primary genital herpes are asymptomatic and up to 80% have no history of symptomatic genital herpes.
    • Herpes gladiatorum occurs among wrestlers, secondary to contact with opponents with active herpesvirus infection.
  • Recurrent infection is termed herpes labialis or recurrent genital herpes. Most individuals have two recurrences each year.
    • Multiple small vesicles, clustered together, appear at the site of premonitory symptoms.
      • The vesicles may arise from normal skin or from an area that has a slight erythematous blush.
      • Vesicles are initially clear, then become cloudy and purulent, dry, and crusty, and heal within 7 to 10 days.
      • The mature lesion consists of grouped vesicles and/or pustules on an erythematous, edematous base.
    • The presence of a yellow or golden crust on older lesions indicates bacterial superinfection.
    • Regional, often tender, adenopathy is almost always present. Lymphangitis and lymphadenitis may be seen, particularly with recurrent lesions of the hands.
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    • The most common sites for lesions are on the face (lips, perioral area, cheeks, and nose) and neck. The next common site is the anogenital area and then the sacrum and buttocks. However, recurrent herpes can be seen anywhere on the skin. It is uncommon for recurrent lesions to be located inside the oral cavity except in the immunocompromised host.
    • Recurrent erythema multiforme is often associated with HSV infection and responds to antiviral prophylaxis.
IV. Assessment
Any doubt concerning the presence of a herpes simplex infection may be clarified by any of the several diagnostic procedures that follow:
  • Skin biopsy of a typical viral vesicle will reveal a characteristic picture: (i) intraepidermal lesion located in the mid-to-upper epidermis, (ii) ballooning degeneration of cells, (iii) acantholytic cells floating free, and (iv) large, multinucleated viral giant cells. Intranuclear inclusions may be seen in the giant cells as well as in other infected epidermal cells.
  • A cytologic smear of the vesicle, to look for giant cells and inclusion bodies, is easily and quickly done. The smears are positive in approximately 75% of virus culture-positive recurrent facial herpes but in only approximately 40% of ulcerative genital lesions. It is important that the earliest vesicle be chosen for biopsy or cytologic smears. Cells from the base of the vesicle will afford the best opportunity to detect the virus. Lesions of herpes simplex, herpes zoster, and varicella will have an identical appearance on biopsy and tissue smear. Exfoliative cytology may be used to detect asymptomatic cervical or vaginal infection, but in pregnant women, it is no substitute for actual viral culture.
  • The virus may be easily and rapidly grown in culture from the vesicle fluid (24 to 48 hours).
  • Specific neutralizing antibody titers will rise after the first week of primary infection and peak at 2 to 3 weeks. Change in antibody titer cannot be used to diagnose recurrent disease.
  • If the appropriate facilities and reagents are available, the following procedures may be carried out if indicated:
    • The virus may be easily identified under the electron microscope.
    • The virus can be demonstrated in tissue specimens using immunofluorescent or immunoperoxidase techniques; both techniques can differentiate herpes type 1, herpes type 2, and varicella-zoster virus.
    • The virus may be typed by appropriate serologic tests.
    • The polymerase chain reaction (PCR) is a very rapid and sensitive technique that is also available for use in certain clinical situations.
    • A new, rapid HSV-2 POCkit is commercially available and is quoted to have high sensitivity.
    • Western Blot assays are also very sensitive and specific; however, they are only available for research purposes.
V. Therapy
  • Specific measures
    • Valacyclovir (Valtrex), a valine ester prodrug of acyclovir (see following text), has a bioavailability three to five times that of acyclovir. This is due to its improved gastrointestinal absorption compared to acyclovir. Valacyclovir is rapidly and almost completely converted to acyclovir after oral administration, with levels comparable to those of intravenous acyclovir. This allows for twice-daily dosing, which may improve compliance and ultimate clinical efficacy. It is more costly than acyclovir. Valacyclovir is the only antiviral agent approved for herpes labialis, for a 3-day course in the episodic treatment of recurrent genital herpes (2). Valacyclovir is indicated for recurrent genital herpes and is administered at 500 mg twice daily for 3 days at the onset of prodromal symptoms or at the first sign of infection. This dosage regimen is as effective as five-times-daily acyclovir in the treatment of recurrent genital herpes in immunocompetent patients (3). Valacyclovir use is contraindicated in immunocompromised patients. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome have occurred in patients with advanced human immunodeficiency virus (HIV) disease, renal
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      transplant, and bone marrow transplant. The most commonly reported adverse events are headache and nausea.
    • Famciclovir (Famvir) undergoes extensive first-pass metabolism to penciclovir after oral administration. Penciclovir is another nucleoside analog that has a mechanism of action similar to that of acyclovir. Compared with oral acyclovir, famciclovir has improved bioavailability as well as a significantly prolonged intracellular half-life, allowing for less frequent dosing. Valacyclovir and famciclovir are similar in their high absorption, bioavailability, renal elimination, minimal drug interaction profiles, safety profiles, and efficacy. Famciclovir is indicated for recurrent genital herpes infections and is administered at 125 mg twice daily for 5 days beginning at the onset of prodromal symptoms or at the first sign of infection. At recommended doses, treatment efficacy is similar to that with acyclovir (4,5). Recent research has shown that oral famciclovir of 250 mg twice daily is effective for the suppression of genital HSV infection (6).
    • Acyclovir, a purine nucleoside analog, revolutionized the treatment of herpes simplex infections. Its safety and specificity are dependent on two factors: (i) a viral enzyme, thymidine kinase, is necessary for the conversion of the drug to its active form and (ii) once activated, acyclovir inhibits a virus-specific DNA polymerase required for viral replication (mammalian DNA polymerase is more substrate specific and therefore unaffected).
      • Intravenous acyclovir (500 mg/m2 IV q8h) is indicated mainly for the treatment of potentially catastrophic herpes infections in the normal (e.g., herpes encephalitis) or immunocompromised host. Treatment promptly aborts new lesion formation, reduces viral titers, promotes healing, and ameliorates pain. Intravenous acyclovir also effectively prevents reactivation of HSV in seropositive immunocompromised patients undergoing chemotherapy or transplantation. Eczema herpeticum and initial herpes infections in immunocompetent patients respond favorably as well.
      • Oral acyclovir (200 mg PO five times daily or 400 mg t.i.d. for 10 days) promotes resolution of primary and first-episode genital herpes infections if begun within 3 days of onset. Acyclovir treatment of the initial attack does not reduce recurrence rates. Patient-initiated early treatment of recurrent genital herpes (<48-hour duration) with acyclovir 800 mg t.i.d. or 200 mg five times a day for 5 days may shorten healing times and reduce the duration and formation of new lesions. If administered as a continuous dosage (400 mg b.i.d.) in patients who have frequent recurrences, acyclovir has been clearly shown to reduce or even prevent outbreaks. Because viral latency is unaffected by therapy, on discontinuation of such “prophylaxis,” recurrent attacks can be expected to resume as before treatment.
        • Prophylactic oral acyclovir of 400 mg b.i.d. started 7 days before or 5 minutes after ultraviolet light exposure in patients with a history of sun-induced herpes labialis has been shown to prevent the development of delayed-onset (2 to 7 days) herpes simplex. If oral acyclovir is started 48 hours after ultraviolet exposure, delayed lesions develop but are less severe. Application of topical acyclovir 5 minutes after light exposure does not reduce the lesion frequency or severity. Recurrent labial herpes in the 26% of individuals who develop immediate (within 48 hours) lesions was unaffected by oral acyclovir therapy. Famciclovir is effective as well (7).
          • Topical acyclovir applied q3h while awake shows a modest effect on primary and first-episode genital herpes infection if begun within 72 hours of onset. It does not abort recurrent episodes even if applied at the first sign of prodromal symptoms. In multiple clinical trials, topical acyclovir was found ineffective.
          • Except for transient renal dysfunction if the intravenous form is administered too rapidly, acyclovir is remarkably free of side effects. The greatest concern is that with widespread use resistant viral strains will render this drug ineffective, especially in the treatment of the more serious infections. Resistance may occur through three mechanisms:
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            (i) mutant viruses deficient in thymidine kinase, (ii) mutants with altered substrate specificity of thymidine kinase, or (iii) mutants with altered viral DNA polymerase enzymes. Thymidine kinase–deficient mutants have been isolated, primarily from immunocompromised hosts. Indiscriminate or inappropriate dispensing of acyclovir should be discouraged.
    • Vidarabine, another nucleoside analog, is effective in the treatment of serious herpes infections. However, it has no apparent superiority over acyclovir, may be less effective in some circumstances (e.g., herpes encephalitis), and has more potential side effects, including anemia and neurotoxicity.
    • Therapy with interferon reduces the virus yield but is ineffective against the latent stage in ganglia.
    • Foscarnet is the only antiviral approved by the FDA for the treatment of acyclovir-resistant HSV infections, a growing problem in the AIDS population. Foscarnet does not require HSV-encoded thymidine kinase. Foscarnet therapy reduces the healing time, pain, and viral shedding. It is administered intravenously, 40 mg/kg every 8 to 12 hours within 7 to 10 days in patients suspected of having acyclovir-resistant herpes simplex infection. Foscarnet is administered for 10 days. Associated side effects include azotemia secondary to nephrotoxicity, hyperphosphatemia, hypocalcemia, anemia, nausea, vomiting, and genital ulceration. Patients may eventually develop resistant strains. Preliminary trials indicate that topical 1% foscarnet cream may have some benefit for the treatment of acyclovir-resistant mucocutaneous HSV infection in patients with AIDS (8).
    • Cidofovir, a monophosphorylated nucleotide analog, does not require viral thymidine kinase phosphorylation to act and therefore has activity against herpes simplex infections with deficient or altered thymidine kinase activity. It is ineffective against rare strains with mutations in DNA polymerase. It is administered intravenously, 5 mg/kg/week for acyclovir-resistant infections in immunocompromised hosts. Associated side effects include nephrotoxicity and neutropenia. Concomitant administration of cidofovir with probenecid and saline hydration decreases the nephrotoxicity. Cidofovir resistance has not been documented.
    • Topical 1% penciclovir cream (Denavir) can reduce the time for healing of recurrent sunlight-induced herpes labialis by 2 days. Pain and discomfort are also diminished (9).
    • Topical 1.8% tetracaine cream can reduce the time for healing of recurrent herpes labialis by 2 days. Significant relief from itching is obtained (10).
    • Docosanol 10% cream (Abreva) was approved by the U.S. Food and Drug Administration (FDA) for over-the-counter topical use for recurrent herpes labialis. In clinical trials, use of docosanol decreased the healing time by 0.7 days, which is similar to the modest benefit obtained with the use of topical penciclovir cream (Denavir) in clinical trials. Docosanol is commonly used as a filler in lipsticks and other cosmetics. Docosanol acts by inhibiting fusion between the human cell membrane and the HSV envelope, thereby preventing viral entry into cells and viral replication.
  • General measures
    • The primary infection is extremely painful, and adequate analgesia is important. If salicylates or nonsteroidal anti-inflammatory drugs (NSAIDs) are inadequate, opiates may be needed for the first 7 to 10 days.
    • When lesions are vesicular, apply cool compresses with tap water or Burow’s solution for 10 minutes t.i.d. to q.i.d.
    • Cleansing mouthwashes [with benzalkonium chloride (Zephiran) 1:1,000 or tetracycline suspension 250 mg/60 mL H2O] both clean and soothe the involved mucous membranes and decrease secondary bacterial superinfections.
    • Vulvovaginitis and genital lesions may be aided by sitz baths in tepid water with or without Aveeno colloidal oatmeal. Women unable to void may sometimes be able to do so while in a bath. If not, intermittent catheterization or a temporary indwelling Foley catheter is necessary.
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    • Apply topical antibacterials such as mupirocin (Bactroban), povidone-iodine ointment, or bacitracin ointment to prevent bacterial superinfection.
    • Early and repeated application of a potent corticosteroid to recurrent lesions will often decrease its severity by inhibiting the inflammatory response. If this modality is used, the periorbital area must be avoided.
    • If a consistent trigger factor for recurrent episodes can be identified, specific measures may be taken to counteract the stimulus (e.g., use of sunscreens). Treatment of primary infections is one of the few instances in which topical anesthetics are justified. Dyclonine hydrochloride (Dyclone), Benadryl elixir, or viscous Xylocaine may be used for oral lesions and benzocaine aerosol (Americaine) or Tronothane ointment may be beneficial symptomatically for the vulvar area. Application should be as frequent as necessary to keep the patient comfortable. The benzocaine preparations may sensitize the skin and should not be used routinely.
    • Prophylactic systemic antivirals should be given before facial surgical procedures (chemical peels, laser surgery, dermabrasion, etc.) if the anatomic area involves the site of a previous HSV infection.
    • Agents that have been shown to be ineffective or that have not been clearly shown to be useful include ethyl ether, chloroform, alcohol, idoxuridine (IDUR), adenine arabinoside (Vira-A), vitamins C, E, and B12, lactobacillus, 2-deoxy-d-glucose, zinc, lysine, povidone-iodine, dye-light (photodynamic inactivation), silver sulfadiazine (Silvadene), nonoxynol-9 cream, and dimethyl sulfoxide (DMSO).
    • Many HSV vaccines have been under investigation; however, most have not shown effectiveness in either the treatment or the prevention of herpes genitalis.
  • Ocular infection. Patients with symptoms of corneal involvement (photophobia, pain) should be examined with a slit lamp. Herpes simplex keratitis is treated with trifluridine (Viroptic), idoxuridine (Herplex, Stoxil), or adenine arabinoside monophosphate (Vira-A); however, herpetic lesions of the lids and the immediate periorbital area, in the absence of ocular involvement, need not be treated with intraocular medication.
    Disease/etiologic agent Initial disease Recurrent disease
    Herpes simplex labialis Valacyclovir 1 g b.i.d. × 10 d Valacyclovir 2 g b.i.d. × 1 d
    Acyclovir 400 mg t.i.d. × 10 d Famciclovir 500 mg t.i.d. × 5 d
    Acyclovir 800 mg t.i.d. × 5 d
    Topical 1% penciclovir q2h × 4 d
    Herpes simplex genitalis Valacyclovir 1 g b.i.d. × 10 d Episodic therapy: famciclovir 125 mg b.i.d. × 5 d
    Famciclovir 250 mg t.i.d. × 10 d Valacyclovir 500 mg b.i.d. × 3 d
    Acyclovir 400 mg t.i.d. × 10 d Suppressive therapy: famciclovir 250 mg b.i.d.
    Valacyclovir 500 mg q.d. (if <10 episodes/year)
    Valacyclovir 500 mg b.i.d. (if 10 or more episodes/year)
    Acyclovir 800 mg t.i.d. × 5 d
    For immunosuppressed: famciclovir 500 mg b.i.d.
    Adapted from Lin P, Torres G, Tyring SK. Changing paradigms in dermatology: antivirals in dermatology. Clin Dermatol 2003;21:426–446; Lin et al. (11).
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References
1. Benedetti JK, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med 1999;131:14–20.
2. Wu JJ, Brentjens MH, Torre G, et al. Valcyclovir in the treatment of herpes simplex, herpes zoster, and other viral infections. J Cutan Med Surg 2003;7:372–381.
3. Tyring SK, Douglas JM Jr, Corey L, et al. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Valaciclovir International Study Group. Arch Dermatol 1998;134:185–191.
4. Wald A, Corey L. Antiviral therapies for long-term suppression of genital herpes. JAMA 1999;281:1169–1170.
5. Diaz-Mitoma F, Sibbald RG, Shafran SD, et al. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group. JAMA 1998;280:887–892.
6. Tyring SK, Diaz-Mitoma F, Shafran AD, et al. Oral famciclovir for the suppression of recurrent genital herpes: the combined data from two randomized controlled trials. J Cutan Med Surg 2003;7:449–454.
7. Spruance SL, Rowe NH, Raborn GW, et al. Perioral famciclovir in the treatment of experimental ultraviolet radiation-induced herpes simplex labialis: a double-blind, dose-ranging, placebo-controlled, multicenter trial. J Infect Dis 1999;179:303–310.
8. Javaly K, Wohlfeiler M, Kalayjian R, et al. Treatment of mucocutaneous herpes simplex virus infections unresponsive to acyclovir with topical foscarnet cream in AIDS patients: a phase I/II study. J Acquir Immune Defic Syndr 1999;21:301–306.
9. Boon R, Goodman JJ, Martinez J, et al. Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: a randomized, double-blind, placebo-controlled trial. Penciclovir Cream Herpes Labialis Study Group. Clin Ther 2000;22:76–90.
10. Kaminester LH, Pariser RJ, Pariser DM, et al. A double-blind, placebo-controlled study of topical tetracaine in the treatment of herpes labialis. J Am Acad Dermatol 1999;41:996–1001.
11. Lin P, Torres G, Tyring SK. Changing paradigms in dermatology: antivirals in dermatology. Clin Dermatol 2003;21:426–446.
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