Immune Response and General Immune Health in Subjects Infected With Herpes Simplex Virus Type 1 (HSV-1)
Immune Response and General Immune Health in Subjects Infected With Herpes Simplex Virus Type 1 (HSV-1)
Primary oral infection with the herpes simplex virus (HSV) typically occurs at a young age,
 is asymptomatic, and is not associated with significant morbidity. After primary oral
 infection, HSV may persist in a latent state in the trigeminal ganglion and later reactivate
 as the more common herpes labialis, or "cold sores." In immunocompetent patients, herpes
 labialis usually is mild and self-limited. However, pain, swelling, and cosmetic concerns may
 prompt physician consultation. Orally administered antiviral agents, such as acyclovir
 (Zovirax) or valacyclovir (Valtrex), have a modest clinical benefit if initiated during the
 prodrome. Topical treatment with 1% penciclovir cream (Denavir) may reduce healing time and
 pain slightly, even if initiated after the prodrome. However, reduction in healing time with
 systemic or topical agents is modest. Squaric acid dibutyl ester (SADBE) is a topical
 immunotherapeutic agent used in the treatment of verruca vulgaris and alopecia areata. A
 study completed by Lee et al of 29 patients with recalcitrant warts demonstrated complete
 clearance in 69% of patients with application every 2-4 weeks. Silverberg et al showed a
 complete clearance in 58% of patients (n=61) when SADBE was applied 3 times weekly. SADBE has
 been reported to cause eczema, lymphadenopathy, blistering, allergic contact dermatitis, skin
 hypopigmentation, a burning sensation after application, and systemic reactions including
 fever and arthralgias. It is hoped that SADBE will offer subjects a safe and effective
 therapeutic option to decrease the frequency and severity of future herpes labialis outbreaks
 through these mechanisms. A placebo-controlled clinical study completed at Massachusetts
 General Hospital showed that squaric acid prevented recurrence of herpetic lesions. The
 effect of SADBE of delaying new herpes labialis outbreaks was highly significant (p<0.01) as
 compared to placebo.
Primary oral infection with the herpes simplex virus (HSV) typically occurs at a young age,
 is asymptomatic, and is not associated with significant morbidity. After primary oral
 infection, HSV may persist in a latent state in the trigeminal ganglion and later reactivate
 as the more common herpes labialis, or "cold sores." Common triggers for reactivation are
 well known and include ultraviolet light, trauma, fatigue, stress, fever, inflammation, and
 menstruation. These lesions affect up to 45 percent of the U.S. population. They classically
 manifest as a well-localized cluster of small vesicles along the vermilion border of the lip
 or adjacent skin. The vesicles subsequently rupture, ulcerate, and crust within 24 to 48
 hours. Spontaneous healing occurs over seven to 10 days. In immunocompetent patients, herpes
 labialis usually is mild and self-limited. However, pain, swelling, and cosmetic concerns may
 prompt physician consultation. Orally administered antiviral agents, such as acyclovir
 (Zovirax) or valacyclovir (Valtrex), have a modest clinical benefit if initiated during the
 prodrome. Topical treatment with 1% penciclovir cream (Denavir) may reduce healing time and
 pain slightly, even if initiated after the prodrome. However, reduction in healing time with
 systemic or topical agents is modest. Squaric acid dibutyl ester (SADBE) is a topical
 immunotherapeutic agent used in the treatment of verruca vulgaris and alopecia areata. During
 a recent FDA Compounding Advisory Committee Meeting, it was recommended that squaric acid
 dibutylester be included on the list of bulk drug substances allowed for use in compounding
 under section 503A of the Federal Food, Drug, and Cosmetic Act. And SADBE has now been so
 listed under section 503A. A study completed by Lee et al of 29 patients with recalcitrant
 warts demonstrated complete clearance in 69% of patients with application every 2-4 weeks.
 Silverberg et al showed a complete clearance in 58% of patients (n=61) when SADBE was applied
 3 times weekly. SADBE has also been used with some success in the treatment of alopecia
 areata. In a review of the literature, Rokhsar et al noted a 50% to 60% success rate of SADBE
 in use for hair re-growth in this population. SADBE has been reported to cause eczema,
 lymphadenopathy, blistering, allergic contact dermatitis, skin hypopigmentation, a burning
 sensation after application, and systemic reactions including fever and arthralgias. A study
 completed by Oglio et al of eight patients treated with SADBE for warts noted only mild and
 well tolerated side effects of erythema, desquamation, cutaneous edema, pruritus, burning,
 and pain. SADBE induces a delayed-type hypersensitivity response which in warts, is believed
 to induce the killing of virally infected cells by cytotoxic lymphocytes. This influx of
 lymphocytes into lesional Page 4 of 14 tissue may also enhance the recognition and processing
 of viral antigens, leading to clonal expansion of effector cells. It is hoped that SADBE will
 offer subjects a safe and effective therapeutic option to decrease the frequency and severity
 of future herpes labialis outbreaks through these mechanisms. A placebo-controlled clinical
 study completed at Massachusetts General Hospital showed that squaric acid prevented
 recurrence of herpetic lesions. The effect of SADBE of delaying new herpes labialis outbreaks
 was highly significant (p<0.01) as compared to placebo.
Inclusion Criteria:

 1. Age ≥18 and <65

 2. Positive test for IgG against herpes simplex virus type 1 (HSV-1).

 3. Groups A and B only: Clinical diagnosis of herpes labialis, which may be made at the
 screening visit based on the patient's self-reported history of symptoms. An active
 herpes labialis outbreak at the time of entry into the clinical trial will neither be
 required nor will be an exclusion criteria.

 4. Group A only: Self report having six or more episodes of herpes labialis in the past
 12 months. Subjects will NOT be told that six-or-more episodes in the previous 12
 months is the entry criterion. Subjects will be asked "How many separate episodes of
 cold sores have you had in the previous 12 months?" They will be included if they give
 an answer of six or more and excluded from Group A if they give an answer of five or
 fewer.

 5. Group A only: At least half of the subject's episodes of the previous 12 months should
 be vesicular in nature and at least half preceded by prodromal symptoms.

 6. Group B only: Self report having exactly 1 or 2 episodes of herpes labialis in the
 past 12 months. Subjects will NOT be told that one or two episodes in the previous 12
 months is the entry criterion. Subjects will be asked "How many separate episodes of
 cold sores have you had in the previous 12 months?" They will be included if they give
 an answer of one or two and excluded from Group B if they give a different answer.

 7. Group C only: Self report having zero episodes of herpes labialis in the past 12
 months. Subjects will NOT be told that zero episodes in the previous 12 months is the
 entry criterion. Subjects will be asked "How many separate episodes of cold sores have
 you had in the previous 12 months?" They will be included if they give an answer of
 zero and excluded from Group C if they give an answer of one or more.

 Exclusion Criteria:

 1. Pregnant or lactating females.

 2. Current or recurrent non-herpetic infection or any underlying condition that may
 predispose to infection or anyone who has been admitted to the hospital due to
 bacteremia, pneumonia or any other serious infection in the last 12 months.

 3. Therapy with glucocorticoid or immunosuppressants at time of recruitment or within
 past 4 weeks prior to the screening visit (including inhaled corticosteroids for
 asthma), except for topical steroids in sites other than face.

 4. History of malignancy (except patients with surgically cured basal cell or squamous
 cell skin cancers).

 5. History of organ transplantation.

 6. HIV-positive status determined by history at screening or known history of any other
 immunosuppressive disease.

 7. Severe co-morbidities (diabetes mellitus requiring insulin, CHF (NYHA class II or
 worse) MI, CVA or TIA within 3 months of screening visit, unstable angina pectoris,
 oxygen-dependent severe pulmonary disease

 8. Known hypersensitivity to Dimethyl sulfoxide (DMSO).

 9. Any condition judged by the investigator to cause this clinical trial to be
 detrimental to the patient.

 10. Subject is currently enrolled in another investigational device or drug trial(s), or
 subject has received other investigational agent(s) within 28 days of baseline visit.

 11. Previous exposure to SADBE (squaric acid or squaric acid dibutyl ester).

 12. Subject has an abnormal skin condition (e.g., acne, eczema, rosacea, psoriasis,
 albinism, or chronic vesiculo-bullous disorder) that occurs in the area ordinarily
 affected by herpes labialis.

 13. Subject has had a vaccine for either HSV-1 or HSV-2.

 14. Group A only: People that have had treatment with anti viral therapy within 2 weeks
 before sensitization dose of SADBE.

 15. Groups B and C only: People that have had treatment with anti-viral therapy any time
 in the past 12 months.