Herpes Simplex VirusesTherapeutics

Question 1

Etiology

Answer 1

HSV type 1
– Commonly termed cold
sores or fever blisters
– Typically associated with
oral lesions (herpes
labialis)
* HSV type 2
– Also known as herpes
genitalia
– Predominantly
associated with genital
lesions

Question 2

Transmission

Answer 2

• Requires close contact with someone who is shedding the
  virus
  – can occur during active outbreak or when asymptomatic
• Inoculation of virus onto susceptible mucosal surfaces (e.g.
  oropharynx, cervix, conjunctivae) or through small cracks in
  skin
• HSV-1: commonly transmitted through oral-to-oral contact
  (virus in saliva, sores, and surfaces in and around the mouth)
• HSV-2: commonly transmitted via sexual activity (oral-genital,
  genital-genital)
• Mother-to-infant transmission

Question 3

Viral Shedding –Herpes Labialis

Answer 3

• Cold sores contagious from prodrome until lesion
  completed healed
  – most contagious when blister bursts or leaks fluid
• Viral titer greater when lesions present but
  asymptomatic transmission possible
  – one study found at least 70% of the population shed
  HSV-1 asymptomatically at least once a month

Question 4

Viral Shedding – Genital Herpes

Answer 4

Up to 70% of new infections attributed to
asymptomatic viral shedding
* Asymptomatic shedding occurs in virtually all
patients with HSV-2
* 50% of viral shedding occurs more than 7 days
before or after a clinical outbreak

Question 5

Pathophysiology of HSV infections

Answer 5

• Two phases of infection:
  – Primary (initial)
  – Secondary (recurrent)
• Initial infection:
  – HSV replicates in cells of epithelium and infects nerve
  ending
  – Transported to nerve (craniospinal) ganglia – latent
  infection
• Trigeminal ganglia (HSV-1) and sacral ganglia (HSV-2)

Question 6

Pathophysiology

recurrence and factors that trigger it

Answer 6

• Recurrence:
  – viral replication reactivated in ganglion
  – spreads to mucosal surfaces through peripheral sensory nerves
• Factors which may trigger recurrence:
  – HSV-1: psychological stress, fatigue, viral illness (e.g., cold or
  influenza), exposure to UV light, local skin trauma, dental treatment,
  menstruation, immune suppression
  – HSV-2: psychological stress, menstruation, local friction, surgery,
  immune suppression

Question 7

HSV and immune response

Answer 7

• HSV-1 and HSV-2 infection induce cell mediated
  immunity and production of antibodies
  – Immune mechanisms modify severity of clinical recurrence
  and reduce HSV replication once reactivation occurs
  – Immune suppressed – ↑ risk for severe herpes

Question 8

slide 12

Answer 8

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Question 9

Signs and Symptoms – Primary Infection
Gingivostomatitis

Answer 9

– Most primary infections are subclinical
– infection determined later through serology or recurrence
– many never have recurrence
– Symptomatic - multiple painful vesicles/blisters and
ulcerative erosions involving lips, oral cavity, pharynx, and
perioral skin
– may also experience systemic symptoms - malaise, fever, muscle
aches, lymphadenopathy
– most common in children
– Healing: days to 2-3 weeks

Question 10

Signs and Symptoms – Primary Infection
Genital Herpes

Answer 10

– Papules and vesicles on the groin, pubic and genital areas,
anus, rectum or buttocks that can rupture and lead to painful
ulcers before healing
– HSV-2 is more severe than HSV-1, and may include systemic
symptoms (40% symptomatic)
– Incubation: ~6 days
– Lesions: 11-12 days
– Symptoms: severe burning pain, itching, dysuria, and vaginal
or urethral discharge

Question 11

Signs and Symptoms- Recurrence

oral lesions

Answer 11

Prodromal period described as tingling, discomfort, burning or itching
may occur 2-24 hours before the appearance of the vesicle in the
location of the eruption

Oral lesions (Cold Sores)
● 20-40% of young adults
seropositive for HSV-1 have
recurrent herpes labialis (typically
2-3 times per year)
● Clusters of small vesicles appear
on a reddened (in some skin tones)
base. Range from 0.5 -1.5 cm
● Vesicles typically last ~ a few days
before they rupture and dry out
● Can also appear in the nose or
eyes

Question 12

Signs and Symptoms- Recurrence
Genital Lesions

Answer 12

● Frequency and severity varies
○ 90% of people with
symptomatic primary HSV-2
experience reactivation
○ Can occur every 2-3 weeks to
every 4-6 months
● Less severe and shorter duration
than primary episode
● May also experience prodrome

Question 13

Visual staging chart for Herpes Simplex Labialis progression.

Diagnosis of herpes labialis

Answer 13

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Diagnosis based on presence of typical signs and
symptoms
– need to rule out other conditions with similar
signs/symptoms (see differential assessments)
* If uncertainty, HSV best confirmed by HSV PCR swab
of lesion (or culture)
* Serology tests typically not used for diagnosis

Question 14

Assessment of Cold Sores

Answer 14

Symptoms- Prodrome? Pain? Redness? Visible lesion?
Characteristics- burning, tingling, itching
History- Primary infection? Already diagnosed? How often are
recurrences?
Onset- Prodrome usually 2-24 hrs before lesion appearance (sooner for
most)
Location- Not always on lips, can appear on skin elsewhere
Aggravating Factors- identifiable triggers?
Remitting Factors- used anything helpful before?
Don’t forget to consider…
Medications
Allergies
Conditions
Social history
(also Pregnancy & breastfeeding

Question 15

Differential Assessment

Answer 15

• Recurrent aphthous stomatitis (canker sores)
• Chicken pox
• Shingles (Herpes zoster)
• Oral cancers (basal cell carcinoma)
• Angular cheilitis
• Impetigo
• Syphilis

Question 16

When to refer patients with cold
sores for further evaluation?

Answer 16

• Age <12 years
• Lesion present for > 14 days
• Lesion appears infected -excessively swollen, red or contain
  pus
• Symptoms of systemic illness (fever, swollen glands)
• Compromised immune system due to medication or disease
  state
• Frequent recurrences - > 6 times per year

Question 17

Assessment – Case Study
* Katie is a 21 year-old female (pronouns: she/her)
* History – tingling started 2 days ago and lesion broke out ~36 hours ago;
has noticed dry lips lately; finds lesion is somewhat painful but more
worried about appearance – feels self-conscious
* PMH: no other medical conditions; previous cold sores – occur ~ once or
twice a year; typically related to stress or sunlight; currently stressed as
she needs to find a job
* Medications: has tried Blistex® lip ointment in the past– does not find it
effective; only taking birth control pill. Would prefer to take a pill to treat
cold sore.
* NKDA
* Non-smoker, social drinker; single (does not have steady partner)

Answer 17

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Question 18

Goals of Therapy

Answer 18

primary and recurrent episodes:
– control severity and duration of symptoms
* goal of suppressive therapy:
– reduce recurrences, frequency and extent of viral
shedding, and decrease disease transmission

Question 19

What to recommend???
What is the evidence???

Answer 19

• Analgesics
• Non-antiviral topical agents
• Antiviral agents
  – Topical
  – Oral

Question 20

Approaches to Treatment: Herpes
Labialis

Answer 20

• Intermittent Episodic Therapy
  – Management of isolated acute episodes
  – Topical or oral therapy can be used
• Chronic Suppressive Therapy
  – Appropriate for patients who are psychologically distressed
  (frequent episodes or severe disease)
  – May be used to decrease transmission to uninfected partners
  – Oral therapy only
• Intermittent Suppressive Therapy
  – Used when recurrences can be anticipated (e.g. known
  precipitating factors)

Question 21

Analgesics

Answer 21

• Oral analgesics
• recommended for moderate-severe pain (e.g., < 3 days)
• acetaminophen, ibuprofen, naproxen
• Topical anesthetics
• useful for mild pain and relatively short time period
• Benzocaine (e.g., Anbesol, Orajel, Zilactin-B)
• Camphor/menthol/phenol (Blistex)
• Lidocaine
• Pramoxine (Gold Bond Medicated anti-itch, Polysporin itch
  relief)

Question 22

Non-antiviral topical agents

Answer 22

Type of Products:
– Protectants: (e.g. petrolatum, zinc oxide, cocoa butter, allantoin or
calamine)
– prevent cracking and excess drying of lips and lesion
– Astringents (e.g. tannic acid)
– not recommended due to excessive drying – lead to cracking,
fissuring, possible bacterial superinfection

Active Ingredient Examples:
○ Zinc (Lipactin®️)– MOA controversial, may prevent virus attachment
to cells; not well studied. Known to be irritating, may be drying.
○ Heparin (also in Lipactin®️) – reduces binding of virus to cellular
target in cell lines tested in lab; no published evidence regarding
safety and efficacy
○ Benzyl Alcohol (Zilactin®️)- similar to a topical anesthetic for pain,
note alcohol is drying

Question 23

ColdSore-Fx®

Answer 23

• Ingredients: 3% Propolis ACF
  – non-medicinal: white petrolatum, mineral
  oil, lanolin, and ethanol
• Propolis is a resinous substance bees collect
  from variety of plant sources
• Dose: apply topically 4-6 times daily until
  healed
• ‘Possibly effective’ for herpes labialis
• Might reduce cold sore duration and
  reduce pain compared to placebo

Question 24

Lysine

Answer 24

• Lysine supplementation not shown to prevent herpes simplex
  infections based on Cochrane review
• “Possibly effective” for herpes labialis at 1-3 g daily (Natural
  Medicines)
• Evidence is mixed
• Another evidence review:
  – Doses < 1 g/day - ineffective for prophylaxis or treatment
  – Doses > 3 g/day - appear to improve subjective experience of the
  disease

Question 25

Oro-labial herpes - Topical Antiviral

Answer 25

Acyclovir 5% cream + hydrocortisone 1% (Xerese®)
Apply 5 times daily for 5 days.
Start during prodrome(earliest sign).
~0.5 day ~ 0.5 day
Acyclovir ointment not as
effective as cream.
Xerese® - prescription
May decrease progression of lesions.
Topical slightly less effective than oral.

Docosanol 10% cream
(Abreva®) Apply 5 times a day until healed (5-10 days). Start during prodrome (earliest sign).
~ 0.5-1 day ~ 0.5 day Over the counter (cost - ~$18-$25)
May help abort attacks.
Topical slightly less effective than oral

Question 26

Oral-Labial HSV - Immunocompetent
* Primary Infections

Answer 26

– Moderate to severe cases – antiviral treatment often
recommended
– Most effective when initiated promptly
– Evidence available suggests significantly decreased disease
duration and period of infectivity in children (duration of
lesions 4 days with acyclovir versus 10 days with placebo)
– Acyclovir 15 mg/kg (up to 200 mg) 5 times a day x 7 days
– Valacyclovir 1 g twice a day x 7 days
– Famciclovir 500 mg twice a day x 7 days

Question 27

Oral-Labial HSV – Immunocompetent
Recurrent (Intermittent Episodic Therapy)

Answer 27

Acyclovir 400 mg 5 times daily for 5 days
(start during prodrome phase)
~ 1 day ~ 0.5-1 day Helps abort lesions.
Ineffective if started once lesions appear.

Valacyclovir 2000 mg very 12 hours x 2 doses
(start during prodrome phase)
~1-2 days ~ 0.5-1 day Helps abort lesions.
Ineffective if started once lesions appear.

Famciclovir 750 mg every 12 hours x 2
doses or 1500 mg once (start during prodrome phase)
~1-2 days ~ 0.5-1 day Helps abort lesions.
Ineffective if started once lesions appear

Question 28

Oro-Labial HSV –Chronic Suppressive
Therapy
* Consider for patients with severe disease and frequent
recurrences (e.g. > 6/year)

Answer 28

Acyclovir 400 mg twice daily
~50% Clinical benefit is small.
Effectiveness beyond 4
months is unknown.

Valacyclovir 500 mg once daily
Decrease of 0.09 episodes per person per month.
Clinical benefit is small. Effectiveness beyond 4 months is unknown.

Question 29

Oro-Labial HSV – Intermittent
Suppressive Therapy

Answer 29

• Used when outbreaks can be anticipated (e.g.
  exposure to UV light, skiers)
• Limited studies support use of oral antiviral therapy
  – may not impact lesions that develop within 48
  hours of UV exposure
• Optimal dose and preferred antiviral agent unknown
• Suggested dose:
• acyclovir 400 mg twice daily starting 12-24 hours before
  exposure and continuing through intense exposure (plus
  sunscreen)

Question 30

Options in Pregnancy

Answer 30

Oral:
* Acyclovir: human & animal data have shown it is
safe in all stages of pregnancy (most data is for
genital herpes)
* Valacyclovir: less data on safety in pregnancy but is
considered an alternative to acyclovir
* Famciclovir: limited pregnancy data in humans
Topical:
* Docosanol: likely safe but limited data in pregnancy
* Topical Acyclovir: considered safe (same as oral)

Question 31

Counselling Tips

Answer 31

Immediate lesion
– Prevention of transmission – wash hands, do not touch
area, do not share creams or items such as lipsticks etc
– Avoid kissing etc until cold sores have healed
– Use of appropriate therapy to reduce symptoms and
speed healing
– Continued use of skin protectant to keep lesions moist
* Triggers
– Discuss avoidance of potential triggers, use sunscreen
– Antiviral creams do not prevent outbreaks
* Recurrent Episode
– Importance of treatment at first sign or symptom of
recurrence