Anti-virals versus vaccination against varicella Vana Papaevangelou,MD Lecturer in Pediatrics Athens...
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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
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?