Management of Herpes Simplex Virus

1 & 2, and Zoster

Elke Backman, PharmD, BCPS
Massachusetts General Hospital

Summer, 2013
 Objectives
Herpes Simplex Virus (HSV 1 & 2) and Herpes Zoster

! Classification, transmission, pathogenesis

! Clinical presentation and diagnosis
! Therapeutic management
n Indications
n Key side effect profiles
n Drug interactions
n Resistance to treatment
 Herpes Infections
Origin: 13751425; late Middle English < Neo-
Latin: cutaneous eruption < Greek hrps, literally,
a creeping (akin to hrpein to creep, spread);
cognate with Latin serpns serpent
 Herpes Infections
! Family: Herpesviridae; subfamily: , ,
! 8 Herpes viruses commonly affect humans:
n Type 1 (HHV-1): mostly assoc. with orofacial
infections, non-sexual contact with infected person
Alpha
n Type 2 (HHV-2): mostly infects genital tract
n Type 3 (HHV-3): Varicella zoster virus (VZV)
n HHV-4: Epstein-Barr virus (EBV) - (Gamma)
n HHV-5: Cytomegalovirus (CMV) - (Beta)
n HHV-6: Roseolovirus -
n HHV-7: Roseolovirus -
n HHV-8: Kaposi's sarcoma-associated herpesvirus -
 Structure of HSV

! Double-stranded DNA
virus
! Capsid = protein cage
! Envelope = Lipid bilayer

The Virion
 Pathophysiology: HSV 1 & 2
! Double stranded DNA virus
n Neurovirulence - can invade and replicate in the
nervous system
n Latency - establishes and maintains latent
infection in nerve cell ganglia.
! HSV 1 trigeminal ganglia
! HSV 2 sacral nerve root ganglia
n Reactivation (can be induced by certain factors)
! Results in symptomatic or asymptomatic infection
and shedding
 ! Viral invasion
of epithelial
cells
! Intracellular
replication
! Virus ascends
along nerve
sheaths
! Ganglia
become
infected within
24 hours

Reproduced with permission from: www.visualdx.com. Copyright

Logical Images, Inc.
Primary & Recurrent Herpes Infections
VIRUS PRIMARY INFECTION RECURRENT INFECTION
HSV-1 Gingivostomatitis Herpes labialis (20% recur)
HSV encephalitis (adults) HSV encephalitis (adults)
Genital herpes Genital herpes
HSV-2 Genital herpes Genital herpes with HSV-2:
Neonatal encephalitis 90% will have at least one
Neonatal herpes recurrence in the first year

VZV Varicella (chickenpox) Herpes zoster (shingles)

 HSV in Immunosuppressed Patients
! Clinical presentation may be more severe and
prolonged
! Atypical presentation
! Recurrences more frequent
n Recurs in 65-80% of seropositive patients receiving induction
chemotherapy for acute leukemia or BMT
! Prolonged viral shedding
! May benefit from higher doses of antivirals and/or
longer duration of therapy
! May be complicated by bacterial superinfection
Neonatal HSV
Disseminated herpes simplex virus (HSV) in the setting of
chemotherapy-induced neutropenia.
Erythema multiforme due to primary Herpes Simplex Virus,
type 1 (HSV-1) infection.
Herpetic whitlow of the left third finger with possible
Staphylococcus aureus superinfection.
 Herpes Gladiatorium
Sad news today for the lad
and my favorite high school
sport. effective immediately,
the minnesota state high
school league suspended all
wrestling for the next eight
days due to an outbreak of
an infectious skin disease
called herpes gladiatorium
yeesh. gladiator herpes?
- Chris Uggen

http://chrisuggen.blogspot.com/2007/01/goffman-wrestling-and-herpes.html
 HSV Transmission &
Immune Response to HSV
! 80% of US adults have had herpes labialis (cold sore)
! 40-60 million people in the US infected with genital
herpes
! Direct contact of susceptible skin
n Symptomatic virus shedding
n Asymptomatic virus shedding (75-80% of virus

shedding): subclinical (infectious); mostly with HSV-2

! Production of antibodies
n Neutralizing antibodies prevent extracellular spread of
the virus, may limit lesion size
n Immune (antibody) reaction often not complete ->
recurrence of outbreaks
 HSV-2 Infection: Clinical Presentation
! Thin-walled blisters; cluster of red bumps, may open into
shallow, painful ulcers
! Most individuals are UNAWARE
! Primary outbreaks:
n May be accompanied by systemic symptoms: fever,
HA, malaise, lymphadenopathy, itching, dysuria
n May take 2-4 wks to heal (peak: 10 days)

n Viremia present in 25% of HSV-2 primary infections

! Recurrent outbreaks:
n Occur at the same site or nearby primary infection

n Rarely associated with systemic symptoms

n Prodrome common prior to recurrence

n Median 4x/year, lasting 4-6 days

 HSV Reactivation (HSV-I, II and III)

Triggers:
Emotional/physical stress
Concurrent infection
Ultraviolet radiation
Physical trauma
Surgery
Menstrual cycles
Hormonal factors
Herpetic gingivostomatitis (primary)
Varicella Zoster Virus (VZV):
1 Infection (Chickenpox)
! Primary VZV infection: inoculation of
infected airborne droplets onto a
mucosal surface
! Initial virus replication in tonsillar and
lymphoid tissue, followed 4 to 7 days
later by a primary viremia.
! Virus spreads to internal organs, and a
secondary, more prolonged viremic
stage occurs 10 to 21 days after the
initial infection. Virus reaches the
cutaneous surface during the
secondary viremia, and results in the
characteristic vesicular rash of
varicella.
! New lesion formation ceases with the
appearance of circulating serum
antibody and a detectable immune
response
VZV: Reactivation
Different dermatomes of the body that can be affected by shingles:

During reactivation,
virus replicates at the
sensory ganglion and
travels peripherally
along sensory nerves
to reach the
mucocutaneous
surface
Courtesy of Vaibhav Parekh, MD
 Herpes Zoster
(= Shingles; HSV-III reactivation)
Viral latency is
maintained through
intact cellular immune
mechanisms. With the
waning of cellular
immunity to VZV
antigens, attributable to
advancing age or
immunosuppression,
virus reactivates and
active virus replication
occurs
 Herpes Zoster Ophthalmicus

Sampathkumar, P, Drage, LA, Martin, DP. Herpes zoster (shingles) and postherpetic
neuralgia. Mayo Clin Proc 2009; 84:274. Copyright 2009 Dowden Health Media.
Therapeutic Management of HSV Infection

! Permanent, treatable; non-curable infection

! Therapeutic goals:
Relieve symptoms
Heal lesion
Reduce frequency of recurrent episodes
Reduce viral transmission
 Antivirals for Alpha Herpes
Infections (HSV-1, HSV-2, and VZV)
Acyclovir Zovirax 5% cream & ointment (topical)
Penciclovir Denavir 1% cream (topical)

Acyclovir Zovirax , generic (oral, IV, topical)

Valacyclovir Valtrex (oral)
Famciclovir Famvir (oral)

Cidofovir Vistide, generic (IV, topical)

Ganciclovir Cytovene (PO, IV)
Foscarnet Foscavir (IV)

Topical agents for eye infections: Trifluorothymidine (trifluridine),

idoxuridine, vidarabine, cidofovir
 Pharmacokinetic Properties
Half-life ADME

Acyclovir 2.5 h A : poor, erratic (10%)

D : Wide
M : small amount by liver
E : Urine (60-90%)
Valacyclovir 2.5 3.3 h A : 54%
(prodrug of D : Wide
(serum levels M : Metabolized to ACV
acyclovir) 3-5x of ACV) E : Urine (89%)
Famciclovir 23h A : 77%
(prodrug of D : 1st pass metabolism
(intracellular M : Metabolized to penciclovir
penciclovir) 7-20h) E : Urine (60%)
 Adverse Effects of Antiviral Agents for HSV

! Acyclovir
n N/V, rash, dizziness
n Rare: anemia, neutropenia, LFTs, pruritis, headache,
hypotension
n IV acyclovir: renal toxicity, crystallization, irritation and
phlebitis at IV site, rare CNS toxicity, rare anemia and
neutropenia
! Valacyclovir same as acyclovir
! Famciclovir
n Headache and dizziness
n Nausea and diarrhea
 Initial Treatment of Herpetic
Gingivostomatitis (Primary)
! Pain control: acetaminophen or ibuprofen
! Petroleum jelly
! "Magic mouthwash," various combinations of
diphenhydramine, Kaopectate or maalox, and/or
viscous lidocaine
! Topical benzocaine (e.g. Zilactin)
! Acyclovir PO for 5-10 days:
n Children: 40-80 mg/kg/day in 3-4 divided doses
n 12 yrs old: 400mg q8h
 Treatment of Orofacial Herpes:
Intermittent Episodic Tx (< 6 episodes/year)
! Topical Therapies (Rx; anti-viral)
n Acyclovir 5% cream (Zovirax)
n Penciclovir 1% (Denavir)

Both inhibit HSV replication in the lesion and decrease

healing times by approximately half a day

! Topical Therapies (OTC)

n Docosanol 10% (Abreva): FDA-approved OTC product
n Zinc Oxydine (Novitra): non-FDA approved OTC product

Both products have no antiviral activity and the effect is

believed to be due to antiinflammatory activity

! Other Topical Therapies (OTC; palliative):

n Campho-Phenique, Carmex, Herpecin L, Neosporin CT, Zilatin L
 Treatment of Orofacial Herpes:
Intermittent Episodic Tx (< 6 episodes/year)

! Acyclovir
n 400 mg TID or 5 times a day x 7d
! Valacyclovir
n 2 g twice a day x 1d
n 500-1000 mg BID x 7d
! Famciclovir
n 1500 mg once
n 250-500 mg BID x 5-7d
! Take with or without food
! Antacids, H-2 blockers or PPIs: No effect
 Prophylaxis for Orofacial Herpes:
Chronic Suppressive

! Of all patients with labial herpes, 5% to 10% experience

frequent recurrences (6 per year).
! Topical Therapy:
n No topical product has shown efficacy as a long

term suppressive therapy (clinical trials small; no

efficacy noted)
! Oral Therapy:
n Acyclovir 400 mg BID

n Valacyclovir 500 - 1000 mg once a day

n Famciclovir 250- 500 mg BID

 Treatment of Genital Herpes
! Initial infection:
n Acyclovir 200 mg 5x per day or 400 mg TID x 7-10d
n Valacyclovir 1000 mg BID x 7-10d
n Famciclovir 250 mg TID x 7-10d
! Symptomatic recurrences:
n Acyclovir 200 mg 5x per day or 400 mg TID x 5d, or
800 mg BID TID x 2-5d
n Valacyclovir 500 mg BID x 3-5d or 1 g daily x 5d,
shortest course: 1 g BID x 1d
n Famciclovir 250-500 mg BID x 5d, or 1 b BID x 1d
 Chronic Suppressive Therapy of
Recurrent Genital Herpes
! Consider higher doses for immunosuppressed
patients or patients with frequent or more
severe recurrences (>9/year)
! Valacyclovir is favored for more severe or
frequent infections
! Acyclovir 400-800 mg BID
! Valacyclovir 500-1000 mg daily, also dosed
250-500 mg BID
! Famciclovir 250-500 mg BID
 Treatment of HSV: Severe Infection

! Consider IV in severe disease or neurologic

complications, suspected CNS infection
! Acyclovir 5-10 mg/kg IV q8h
! Dilute to 5mg/ml (10mg/ml for central line)
! Infuse over at least one hour
! Renally adjusted dosing:
n 5 - 10 mg/kg Q24h for CrCl 10-50 ml/min
n 2.5 - 5 mg/kg Q24h for CrCl < 10 ml/min
! Nephrotoxicity due to crystalluria and renal tubular
damage
! Monitor for phlebitis, n/v/d/HA, rash, LFTs, SCr, rare
neurotoxicity, rare anemia or neutropenia
HSV and Resistance to Antiviral Therapy

! Immunocompetent individuals:
prevalence of ACV-resistant HSV = 0.3%
! Immunocompromised individuals:
prevalence of ACV-resistant HSV = 4-7%
! Resistant strains:
Generated in local mucosal replicating sites
Most are deficient in thymidine kinase
IV foscarnet or cidofovir

ACV = Acyclovir
 Patient Counseling
! Emotional support
! Education
n HSV-1 genital infection is frequently acquired by
receiving oral sex in a monogamous relationship
n Abstaining from sex during outbreaks
n Asymptomatic shedding
n Inform partner if HSV-2 (+), even if asymptomatic
n Using condoms consistently and correctly
n Taking antiviral therapy daily to decrease viral
shedding and outbreaks
 Prevention
www.sexualityandu.ca

Barrier Methods
Prevention approaches are important to decrease the transmission of STIs
Male condom:
Male condom A male condom prevents the exchange
of fluids during intercourse.

A male condom is a sheath placed on an erect penis to prevent the

exchange of fluids between partners during intercourse or oral sex. Latex
condoms offer protection against the transmission of many STIs.
Polyurethane condoms are also highly effective, but are more prone to
breakage. Condoms made from sheep membrane are not effective
barriers.

Female condom

Illustrations: 2007 GCT II Solutions and Enterprises Ltd.

A female condom is a polyurethane sheath worn inside the vagina during
sexual intercourse. It has two rings an inner one at the closed end, Female condom:
The female condom is inserted into the
used to insert the condom and hold it in place behind the pubic bone; and vagina prior to entry by the penis.

an outer ring that remains outside the vagina. It should not be used with a
male condom.

Use of the female condom has been reported for anal sex. Condom
manufacturers do not recommend such use and little evidence exists to
support its efficacy.
 Prevention
www.sexualityandu.ca

Barrier Methods
Prevention approaches are important to decrease the transmission of STIs

Cutting a condom to make a dental dam

Dental dam

A dental dam is a thin square of latex that can be used as a shield

during oral sex. The dam is placed over a womans vulva, acting as a
barrier between her genitals and her partners mouth. They can also
be used as a barrier when oral sex is performed on a partners anus.
1

Dams are for sale in some pharmacies and sexual-health clinics, but
can also be made using a condom or a latex glove. Simply unroll the
condom, cut off the tip and base and cut down the length of the tube.
Then unroll the condom into a rectangular sheet.

Illustrations: 2007 GCT II Solutions and Enterprises Ltd.

2

3
 Treatment of Chickenpox
! Bathing, closely cropped fingernails
! Calamine lotion, oatmeal baths, diphenhydramine or
loratidine for itching
! AAP recommends oral acyclovir with 24h of onset for:
n Adolescents and adults
n High-risk patients (e.g. premature infants, children with
bronchopulmonary dysplasia)
! Children 2-16 yrs: Acyclovir PO 20 mg/kg QID x 5 days
(maximum 800 mg daily)
! Adults and adolescents: Acyclovir up to 800mg 5 x a day
 Treatment of Acute Herpes Zoster
Infection
! Treatment should begin within 72 hours of rash onset
n duration of viral shedding, new lesion formation, and pain
n Accelerates healing and likely reduces neural damage
! Acyclovir 800 mg 5x daily for 7-10d; IV acyclovir is
indicated for severe or disseminated disease
! Valacyclovir 1000 mg TID x 7d
! Famciclovir 500 mg TID x 7d
! Topical antiviral therapy lacks efficacy not
recommended
! AEs: Nausea, vomiting, HA similar to placebo
 Antiherpes Agents: Drug interactions
! Acyclovir:
n Additive effects with other nephrotoxic agents
(e.g. cyclosporine)
n Severe somnolence reported with zidovudine
n Mycophenolate potentiates antiherpes activity
n Methotrexate: ACV may reduce renal clearance of
other drugs eliminated by active renal secretion
n May increase normeperidine levels
! Valacyclovir:
n Same as acyclovir
Supplemental Antiviral Therapy (Herpes
Zoster): Corticosteroids
! 2-3 week tapering dosage evaluated in 2 well-designed
clinical trials [1,2]
n Did not reduce prolonged pain
n Beneficial effects on acute pain, some cutaneous end points,
including time to uninterrupted sleep, return to normal activities,
cessation of analgesic therapy
! Subsequent meta-analysis of 5 RCTs showed no benefit[3]
! AEs: GI, edema, granulocytosis, 2 infections
! Prednisone 60mg/d, taper over 10-14 days
! Avoid: HTN, DM, gastritis
1. Whitley RJ et al. Ann Intern Med. 1996;125(5):376
2. Wood MJ et al. NEJM 1994;330(13):896
3. He L. Cochrane Database Sys Rev 2008; CD005582
 Treatment of Post-Herpetic Neuralgia

! Severe acute pain is a risk factor for PHN

! TCAs: Amitriptyline, desipramine, nortriptyline
Sedation and dry mouth
screening ECG recommended for pts > 40 years old
! Amitriptyline 25mg once daily for 3 months
beginning within 48h rash onset
Reduced the incidence of PHN at 6 months by at least 50%
[1,2]

! Up to 3 weeks for onset of efficacy of TCAs

! Venlafaxine & duloxetine
1. Bowsher D. J Pain Symptom Mgmt 1997;13:327-31.
2. Dworkin RH. Lancet 1999;353:1636-7.
 Treatment of Post-Herpetic Neuralgia

! Opioid analgesics
n Oxycodone resulted in significant in pain (67% in placebo vs
11% treatment group) [1]
n Long-acting agents are preferred
n Morphine, methadone also used
! Gabapentin 300mg TID, taper up to 1800-3600mg daily
! Pregabalin: Improved PK, reduce PHN by 30% [2],
150-300mg daily
! Valproic acid

1. Watson CP et al. Neurology 1998;50(6):1837-1841.

2. Dworkin RH et al. Neurology 2003;60(8):1274-1283.
 Treatment of Post-Herpetic Neuralgia

! Topical capsaicin & lidocaine patches not useful in

acute setting
! Capsaicin: Cream, gel, lotion, patch (Salonpas,
Qutenza)
n Apply cream QID
n Can cause burning, stinging, erythema
n Depletes substance P, prevents reaccumulation
! Lidocaine patch: up to 3 patches may be applied,
remove after 12 hours

1. Watson CP et al. Neurology 1998;50(6):1837-1841.

2. Dworkin RH et al. Neurology 2003;60(8):1274-1283.
 Varicella Virus Vaccine (Varivax)
! VARIVAX is the single-antigen varicella vaccine
! ProQuad , or MMRV, is a combination vaccine of
measles, mumps, rubella, and varicella.
! Both vaccines contain live, attenuated virus.
! Children 12 months through 12 years of age should
receive two 0.5ml doses of varicella-containing vaccine
administered subcutaneously, separated by at least 3
months.
 Herpes Zoster Vaccine (Zostavax)

Large RCT with live attenuated VZV vaccine in

immunocompetent adults >60 years demonstrated a
reduction in the incidence of acute herpes zoster by
more than 50% and a reduction in the incidence of
postherpetic neuralgia of 67%.
Licensed by the FDA in 2006 adults 60 yrs
Avoid in pregnant women or individuals with anaphylaxis
to gelatin or neomycin
Live virus vaccine: Not recommended in AIDS, leukemia,
lymphoma, pts on immunosuppressive therapy
Marin M, Gris D, Chaves SS, Schmid S, Seward JF, Advisory Committee on Immunization
Practices, et al. Prevention of varicella: recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep. Jun 22, 2007.
 Helpful Resources
Organization Websites
US Centers for Disease Control cdc.gov/std/herpes
(CDC) and Prevention cdc.gov/flu
cdc.gov/vaccines
cdc.gov/shingles
American Herpes Foundation herpes-foundation.org

The International Herpes ihmf.org

Management Forum
The American Social Health ashastd.org
Association
The American Chronic Pain theacpa.org
Association

Thank you!