Acute Episodic Therapy for Herpes Labialis

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• Acute Episodic Therapy for Herpes Labialis
• Topical therapy
• Topical therapy with aciclovir cream (five times
  daily for 4 days) or penciclovir cream (2-hourly
  during the day for 4 days) can be used to shorten
  the duration of signs and symptoms of herpes
  labialis (Category 1 recommendation
• Oral therapy
• For acute treatment, oral aciclovir (200400 mg
  five times daily for 5 days), famciclovir (500 mg
  three times daily for 5 days), or valaciclovir
  (2000 mg twice daily for 1 day), should be used
  to shorten the duration of herpes labialis
  (Category 1/2 recommendation)
• Combination therapy with famciclovir 500 mg three
  times daily plus topical 0.05 fluocinonide gel
  twice daily for 5 days may be used to decrease
  lesion severity (Category 3 recommendation)
• Continuous suppressive therapy
• Long-term antiviral prophylaxis with oral
  aciclovir 400 mg twice daily, or valaciclovir 500
  mg once daily, should be offered to prevent
  recurrences of herpes labialis in patients with
  severe and/or frequent disease (Category 2
  recommendation)
• Topical agents are ineffective for prophylaxis of
  herpes labialis and should be avoided (Category 2
  recommendation)
• Genital HSV therapyTopical therapies are not
  recommended

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Sexually Transmitted Diseases Treatment
Guidelines --- 2002

• Topical antiviral therapy for genital herpes
  offers minimal clinical benefit, and its use is
  not recommended

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Herpes Labialis Difficulties with Treatment

• Lesion maturation within 8 hours
• Virus present for about 3 days
• Variability in disease

Difficulties with Topical Formulations

• Formulations that penetrate skin without being
  irritant
• ACV cream better than ointment
• Cream approved in Europe for gt decade but in USA
  for only 3 years

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Skin Penetration of ACV and PCV

• Stratum corneum is a significant barrier
• Removing increases penetration by 4001000 fold
• ACV cream penetrates better than ointment

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Lesion Stages
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Antivirals

• Aciclovir like nucleoside analogues
• Aciclovir
• 5 ACV ointment ( in polyethylene glycol, PEG),
  Zovirax
• 5 ACV cream ( in propylene glycol, sodium lauryl
  sulfate)
• Zovirax
• Penciclovir
• 1 PCV cream ( in propylene glycol other
  inert), Denavir
• Docosanol
• 10 cream, Abreva
• Only FDA approved OTC

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Effect of Short Course Oral Valaciclovir

• Two multicentre randomized double blind studies
• Treatment
• Valaciclovir 2 g 2X/one day
• Valaciclovir 2 g 2X day 1 1 g 2X day 2
• Self-initiated at earliest prodrome and prior to
  1st sign
• Present to clinic within 24 h
• Spruance et al. AAC 2003471072

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Oral Valaciclovir Effect on Healing
P lt.01
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Oral Valaciclovir Effect on Pain
P lt.01
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Effect of Oral Valaciclovir on Healing

• See Figure 1, Spruance S et al. AAC 2003471072
• Click here to link to article text

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Effect on Development of Classic Lesions

• A greater proportion of treated subjects
  (6.48.5) did not develop lesions
• (P0.10.04)

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Aciclovir

• Zovirax cream 5
• Approved only for cold sores
• Propylene glycol
• 5x/day for 4 days
• Zovirax ointment 5
• Approved for initial genital herpes and non life
  threatening lesions in immunocompromised
• Polyethylene glycol (PEG)
• 6x/day for 7 days

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Effect of ACV Cream

• Two large double blind randomized studies
• ACV 5 cream in vehicle control (4 propylene
  glycol 1 sodium lauryl sulfate)
• Self initiated within 1 h of recurrent episode
  (prodrome or first clinical sign)
• Present to clinic within 12 h
• Treated 5 x/day for 4 days
• Follow daily
• Spruance et al. AAC 2002462238

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Effect of ACV Cream on Healing
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Effect of ACV Cream on Pain
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Effect of ACV Cream on Healing

• See Figure 3, Spruance S et al. AAC 2002462238
• Click here to link to article text

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Effect on Development of Classical Lesions

• Topical ACV cream did not prevent the development
  of classical lesions

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Effect of Penciclovir Cream

• Large multicentre double blind placebo controlled
• Penciclovir 1 vs. vehicle control
• Self-initiated within 1 h of first sign or
  symptom
• Present to clinic within 24 h
• Treated q2h x 4 days
• Followed daily
• Spruance et al. JAMA 19972771374

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Effect of Penciclovir
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Effect of Penciclovir on Healing

• Lesion healing 0.7 day faster for
  penciclovir-treated patients compared with those
  given control cream (median, 4.8 days vs 5.5
  days Plt.001
• Pain and lesion virus shedding resolved more
  quickly for penciclovir-treated patients (Plt0.05)
• Efficacy of penciclovir cream apparent when
  treatment initiated during prodrome or late
  symptomatic stages
• Efficacy of penciclovir cream seen in all
  clinical and laboratory measures of the disease
  (lesion healing, pain resolution, and cessation
  of viral shedding)

Spruance S et al. JAMA 19972771374
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Effect on Development of Classical Lesions

• Topical penciclovir did not prevent the
  development of classical lesions.

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Topical ACV vs. PCV

• ACV 3 vs. PCV 1
• 248 subjects randomized
• No significant differences in resolution but
  P.08 for PCV
• Clinical scores lower for PCV on Days 5 and 7
• Lin et al. J Dermatol Treat 20021367

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Are All ACV Creams Equal

• Should contain 40 propylene glycol (PG) for
  optimum protection
• 80 of generic ACV creams contained lt20 PG
• A dose response to PG concentration was
  identified with up to 7.5 fold differences in ACV
  concentrations in human skin
• Trottet et al. Int J Pharm
  200530463

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Effect of Docosanol

• 2 carbon saturated primary alcohol that effects
  one or more steps of viral entry (especially
  fusion) and may also have other antiviral effects
• Two double blind placebo controlled multicentre
  trials
• 10 docosanol cream
• Placebo polyethylene glycol
• Treatment begun within 12 h of episode (prodrome
  or erythema stage) at the clinic,
• Applied 5 x day until healing (max 10 days)
• Sacks et al. J Am Acad Derm 200145222

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Effects of Docosanol
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Summary
.6
.7
1.0
.7
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Antiviral Steroid

• Rationale
• Virus is present for limited time
• Lesions last for longer than virus persists
• Immune response may be responsible for most of
  clinical symptoms

Therefore combination of antiviral effect and
immunomodulatory effect may be optimal
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Oral Famciclovir Steroids

• Famciclovir 500 mg tid x 5 days fluocinonide
  .05 tid x 5 days vs. famciclovir
• UV induction
• Combination decreased
• Lesion size 49 vs. 162 mm2
• with Pain 59 vs. 100
• Healing 5.3 vs. 8.9 days
• Spruance et al. J Infect Dis 20001811906

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5 ACV 1 Hydrocortisone

• In animal models 5 ACV 1 hydrocortisone is
  optimal
• UV induction model
• Treatment began 2 days after UV
• 6 x daily for 5 days.
• Evans, et al. AAC 2002461870

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Effect of ME-609 on UV Induced Lesions

• See Figure 1, Evans TG et al. AAC 2002461870
• Click here to link to article text

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Effect of ME-609 on Healing

• See Figure 3, Evans TG et al. AAC 2002461870
• Click here to link to article text

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Effect of ME-609 on Healing

• See Figure 2, Evans TG et al. AAC 2002461870,
  2002
• Click here to link to article text

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Immunomodulators and HSV

• Rationale improving the immune response would
  decrease recurrent disease
• Evaluations using the guinea pig model of genital
  HSV showed imiquimod and resiquimod reduced the
  frequency of recurrences during and after therapy
• A pilot study in humans showed an increase in
  time to next recurrence of genital lesions

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Effect of Imiquimod on Herpes Labialis

• Double blind randomized trial
• Imiquimod 5 (approved for use in genital warts)
• Applied on Day 1,3 and 5 (after presenting within
  48 h of lesion)
• Applied at bed time and left for 8 h

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Effect of Imiquimod on the Lesion
Bernstein et al. CID 200541808
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Time to Next Recurrence

• Median time until next recurrence increased from
  50 days in the vehicle group to 91 days in the
  imiquimod group (P.018)
• Imiquimod 5 cream associated with a delay in the
  time to first recurrence of herpes labialis
  lesions

Bernstein D et al. CID 200541808
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