Immune Response and General Immune Health in Subjects Infected With Herpes Simplex Virus Type 1 (HSV-1)
Condition: HSV; Herpes Labialis
MeSH terms: Herpes Simplex; Herpes Labialis
Study type: Interventional
Phase: Phase 1

Summary: 
      Subjects were recruited who were positive for antibody against herpes simplex virus type 1
      (HSV-1) and self-reported having in the previous 12 months

        -  6 or more herpes labialis outbreaks (group A),

        -  1 or 2 outbreaks (group B), or

        -  zero outbreaks (group C). Twelve subjects in each group were recruited. Blood was
           collected from these persons and peripheral blood mononuclear cells (PBMCs) isolated and
           tested for proliferation in vitro when stimulated with HSV-1-infected cell extracts,
           free HSV-1 virus, or Candida albicans extract. Candida albicans is a ubiquitous
           infectious fungus and its extract is used as a test of general immune response. RNA was
           also isolated from the PBMCs after incubation in the three stimuli and expression of 41
           immune-related genes quantified by quantitative real-time PCR. Also serum anti-HSV-1 IgG
           levels were quantified.

      After the blood collection on day 1, the persons in group A (frequent cold sore sufferers)
      were treated with a single topical application of 2% squaric acid dibutyl ester (SADBE) in
      DMSO, applied to the inner aspect of the upper arm. These subjects returned on days 15 and 57
      for blood collection, and their PBMCs were tested again on those dates for proliferation in
      vitro against the same stimuli and for gene expression and for serum anti-HSV-1 IgG levels.
    

Detailed description: 
      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.
    

Intervention name(s): Squaric Acid Dibutyl Ester
Intervention type(s): Drug
Intervention description(s): 2% squaric acid dibutyl ester (SADBE) (Supplied by Squarex) is topically applied to the inner aspect of the upper arm of the subject and covered with Tegaderm. Subject is advised to wash it off after 3 hours.
Other intervention name(s): SADBE
Intervention MeSH terms: Squaric acid dibutyl ester
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will be recruited in three groups, all of whom are infected with HSV-1, as shown by having IgG against HSV-1:
x Group A: 12 subjects with 6 or more herpes labialis outbreaks in the past 12 months x Group B: 12 subjects with 1 to 2 outbreaks in the past 12 months x Group C: 12 subjects with zero outbreaks in the past 12 months Subjects in group A will receive 2% SADBE dose on the arm after their initial blood samples are obtained. Group A subjects will have blood collected and tests repeated 2 and 8 weeks later.
Subjects in Groups B and C will be matched to the subjects in Group A so that demographic characteristics (i.e., gender distribution, age and weight) are within broadly similar ranges.
Masking: None (Open Label)
Primary purpose: Screening
Keywords: Squaric Acid; Squaric acid dibutyl ester; cold sores