Anti-virals versus Anti-virals versus vaccination against varicellavaccination against varicella

Vana Papaevangelou,MDVana Papaevangelou,MDLecturer in PediatricsLecturer in Pediatrics

Athens Medical SchoolAthens Medical School

Varicella (chickenpox)Varicella (chickenpox)

Common, highly contagious but usually Common, highly contagious but usually mild disease of childhood.mild disease of childhood.

Complications in 5-10 %.Complications in 5-10 %. Hospitalization rate 8-10/10Hospitalization rate 8-10/104 4 children, children,

highest in children <4 years old.highest in children <4 years old. Increased incidence of complications in Increased incidence of complications in

neonates, adolescents, adults and neonates, adolescents, adults and immunocompromised patients. immunocompromised patients.

Acyclovir for chickenpox: when ?Acyclovir for chickenpox: when ?

Acyclovir has been used since 1980’s in Acyclovir has been used since 1980’s in

neonates, immunocompromised children and neonates, immunocompromised children and

adults.adults.

1992:FDA approved oral acyclovir for tx of 1992:FDA approved oral acyclovir for tx of

chickenpox in normal children.chickenpox in normal children.

Klassen TP, et al. The Cochrane collaboratiKlassen TP, et al. The Cochrane collaboration 2005on 2005

Acyclovir for treating varicella in Acyclovir for treating varicella in normal childrennormal children

Meta-analysis of randomized placebo Meta-analysis of randomized placebo controlled trials, 3 studies included; controlled trials, 3 studies included; Balfour 1990, 1992 and Dunkle 1991.Balfour 1990, 1992 and Dunkle 1991.

Acyclovir given Acyclovir given withinwithin 24 hours: 24 hours: 1. reduced days of fever (-1.1 days)1. reduced days of fever (-1.1 days)

2. reduced number of lesions (-76 lesions)2. reduced number of lesions (-76 lesions)

Klassen T, et al. The Cochrane CollaboratiKlassen T, et al. The Cochrane Collaboration 2005on 2005

Acyclovir for treating varicella in Acyclovir for treating varicella in normal childrennormal children

Did not significantly reduce:Did not significantly reduce:1.1. Days to new lesionsDays to new lesions

2.2. Days to relief of itchingDays to relief of itching

Moreover acyclovir does not reduce Moreover acyclovir does not reduce complication rate or contagiousness.complication rate or contagiousness.

Acyclovir for chickenpox: when ?Acyclovir for chickenpox: when ?

AAP recommends (1993):AAP recommends (1993):

1.1.Children > 12 years oldChildren > 12 years old

2.2.Chronic pulmonary/cutaneous conditionsChronic pulmonary/cutaneous conditions

3.3.Receiving long-term salicylate therapyReceiving long-term salicylate therapy

4.4.Receiving short, intermittent or Receiving short, intermittent or

aerosolized steroidsaerosolized steroids

5.5.Secondary household cases Secondary household cases

Anti-virals for chickenpoxAnti-virals for chickenpoxCONCLUSIONSCONCLUSIONS

Varicella in normal host Varicella in normal host oral acycloviroral acyclovir

Immunocompromised patients have high incidence Immunocompromised patients have high incidence

of complications and viral resistance:of complications and viral resistance:

IV acyclovirIV acyclovir

IV foscarnet if resistance suspectedIV foscarnet if resistance suspected

P.O. valacyclovir, famciclovir in small studies but not as P.O. valacyclovir, famciclovir in small studies but not as

yet approved for chickenpox.yet approved for chickenpox.

Acyclovir for chickenpox Acyclovir for chickenpox doses doses Immunocompetent childrenImmunocompetent children

P.O.: 80mg/kg/day QID for 5 days P.O.: 80mg/kg/day QID for 5 days I.V.: 30mg/kg/day or 1500mg/mI.V.: 30mg/kg/day or 1500mg/m22/day TID /day TID

for 7for 710 days10 days

Immunocompetent adultsImmunocompetent adults P.O.: 800 mg x5 times/day for 5 daysP.O.: 800 mg x5 times/day for 5 days

Immunocompromised childrenImmunocompromised children P.O.: 250-600mg/mP.O.: 250-600mg/m22/dose 4/dose 45 times/day5 times/day I.V.: same as in immunocompetent childrenI.V.: same as in immunocompetent children

Immunocompromised adultsImmunocompromised adults I.V.:1500mg/mI.V.:1500mg/m22/day TID for 7/day TID for 710 days10 days

Herpes Zoster in the USHerpes Zoster in the US

10%10%25% chance of a healthy person 25% chance of a healthy person

developing herpes zoster during a lifetimedeveloping herpes zoster during a lifetime

About 600,000 cases annually About 600,000 cases annually

1.31.34.8 cases per 1000 population annually4.8 cases per 1000 population annually

Risk factors: advancing age, malignacy, Risk factors: advancing age, malignacy, immunodeficiencyimmunodeficiency..

Arvin AM. In: Knipe DM, Howley PM, eds. Fields Virology. Vol 2. 4th ed. 2001:2731-2767.Viral diseases. In: Odom RB, James WD, Berger T, eds. Diseases of the Skin. 9th ed. 2000:473-491.International Herpes Management Forum. PPS Europe Ltd; 1993:4.

Herpes Zoster: Herpes Zoster: IncidenceIncidence increases with advancing age increases with advancing age

Age (years)

14 15-24 25-34 35-44 45-54 55-64 65-74 750

100

200

300

400

500In

cide

nce/

100,

000

Pe

rso

ns/Y

ear

FemalesMales

International Herpes Management Forum. PPS Europe Ltd; 1993:4.

Herpes Zoster: Herpes Zoster: definitions of pain definitions of pain

Acute-phase pain Postherpetic neuralgia (PHN)

Onsetof rash

Rashhealed

Painresolves

Zoster-associated pain (ZAP)

HERPES ZOSTER: HERPES ZOSTER: WHO TO TREAT?WHO TO TREAT?

(Within 72 hours from onset)(Within 72 hours from onset) Not recommended for healthy children.Not recommended for healthy children. Immunocompetent adults with zoster Immunocompetent adults with zoster

ophthalmicus or (+)risk factors for PHN:ophthalmicus or (+)risk factors for PHN: Advanced ageAdvanced age Severe painSevere pain Severe rashSevere rash Adverse psychological factorsAdverse psychological factors

ALL adults ???ALL adults ??? All immunocompromised patients.All immunocompromised patients.

Antiviral therapy:Antiviral therapy: nucleoside analogsnucleoside analogs

Valaciclovir

NH2

CH(CH3)2CH2OCH2CH2OC

HN

O

N

H

C

H2N O

N

N

Famciclovir

NH

NH2

CH2

CH2

CH2

CH3C

CH3C-O-CH2

O

N

N

N

C

O

OH

Acyclovir

NH

NH2

CH2CH2

CH2HO

O

ON

N

N

Penciclovir

2

2

CH2

2

2

H

N

H

Brivudin

VALCICLOVIR (Valtrex)VALCICLOVIR (Valtrex)

Converted to acyclovir. Converted to acyclovir. Bioavailability 54.5%.Bioavailability 54.5%. Dose: 1 gm X 3/day.Dose: 1 gm X 3/day. Caution in patients with renal disease.Caution in patients with renal disease. Caution in immunocompromised pts.Caution in immunocompromised pts. Not approved for children. Not approved for children. Not approved in immunocompromised Not approved in immunocompromised

patients.patients.

FAMCICLOVIR (Famvir)FAMCICLOVIR (Famvir)

Converted to penciclovir.Converted to penciclovir. Bioavailability 77%.Bioavailability 77%. Dosage:250Dosage:250500mg X3/day x7 days 500mg X3/day x7 days Acyclovir resistant mutants also resistant to Acyclovir resistant mutants also resistant to

penciclovir.penciclovir. Not approved for children.Not approved for children.

The efficacy of famciclovir has not been The efficacy of famciclovir has not been established for the treatment of herpes established for the treatment of herpes zoster in immunocompromised patients.zoster in immunocompromised patients.

Herpes Zoster:Herpes Zoster: Famciclovir 500 mg TID Famciclovir 500 mg TID vsvs Placebo Placebo

Tyring S, et al. Ann Intern Med. 1995;123:89-96..

Famciclovir 500 mg TID significantly reduced the duration of PHN by a median of 100 days in patients 50 years

Time to Loss of PHN

140

60

0

Med

ian

Day

s to

Los

s of

PH

N

180

100

All PatientsP=.02

120

80

40

20

160

Patients 50 YearsP=.004

FCV 500 mg TID

Placebo

63

119

63

163

BRIVUDIN (Brivir, Zerpex, Zostex, Zonavir)BRIVUDIN (Brivir, Zerpex, Zostex, Zonavir)

BRIVUDINBRIVUDIN

Rapid absorption, not affected by foodRapid absorption, not affected by food Bioavailability Bioavailability 30% 30% Long half-life Long half-life Elimination mainly by renal route (65%)Elimination mainly by renal route (65%) No nephrotoxicityNo nephrotoxicity Administered: 125 mg Administered: 125 mg once dailyonce daily Best complianceBest compliance

Anti-virals for herpes zosterAnti-virals for herpes zoster(Within 72 hours from onset)(Within 72 hours from onset)

Immunocompetent adults (P.O.):Immunocompetent adults (P.O.): Acyclovir:Acyclovir: 800mg x 5 x 7 days 800mg x 5 x 7 days Valciclovir:Valciclovir: 1gm x 3 x 7 days1gm x 3 x 7 days Famciclovir:Famciclovir: 250-500mg x 3 x 7 days250-500mg x 3 x 7 days Brivudin:Brivudin: 125mg x 1 x 7 days125mg x 1 x 7 days

Immunocompromised patients:Immunocompromised patients: IV Acyclovir:IV Acyclovir: 1500mg/m1500mg/m22/day TID 7-10d/day TID 7-10d PO antivirals ???? PO antivirals ????

Anti-virals for HZ Anti-virals for HZ

DrugDrug Doses/dayDoses/day Year Year approvedapproved

Cost Cost (euro)(euro)

Acyclovir Acyclovir (Zovirax)(Zovirax) 55 1980s1980s 64.2264.22

Valciclovir Valciclovir (Valtrex)(Valtrex) 33 19951995 110.96110.96

Famcyclovir Famcyclovir (Famvir)(Famvir) 33 19981998 110.94 110.94

170.79170.79Brivudin Brivudin (Brivir)(Brivir) 11 20022002 108.66108.66

VZV INFECTIONVZV INFECTIONANTIVIRALSANTIVIRALS VERSUS VERSUS VACCINATIONVACCINATION

Chickenpox in normal Chickenpox in normal hosts at high risk for hosts at high risk for complications.complications.

Herpes zoster in Herpes zoster in adults.adults.

Immunocompromised Immunocompromised children and adults.children and adults.

Postexposure Postexposure prophylaxis prophylaxis onlyonly in in immunocompromised immunocompromised +/- VZIG.+/- VZIG.

All healthy children.All healthy children. Post-exposure Post-exposure

prophylaxis in prophylaxis in sensitive children sensitive children and adults.and adults.

Immune adults? Immune adults? (reduction of HZ). (reduction of HZ).

Before organ Before organ transplantation?transplantation?