Anti-virals versus vaccination against varicella

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

2. Varicella (chickenpox) • Common, highly contagious but usually mild disease of childhood. • Complications in 5-10 %. • Hospitalization rate 8-10/104 children, highest in children <4 years old. • Increased incidence of complications in neonates, adolescents, adults and immunocompromised patients.

3. Acyclovir for chickenpox: when ? • Acyclovir has been used since 1980’s in neonates, immunocompromised children and adults. • 1992:FDA approved oral acyclovir for tx of chickenpox in normal children.

4. Acyclovir for treating varicella in normal children • Meta-analysis of randomized placebo controlled trials, 3 studies included; Balfour 1990, 1992 and Dunkle 1991. • Acyclovir given within 24 hours: 1. reduced days of fever (-1.1 days) 2. reduced number of lesions (-76 lesions) Klassen TP, et al. The Cochrane collaboration 2005

7. Acyclovir for treating varicella in normal children • Did not significantly reduce: • Days to new lesions • Days to relief of itching • Moreover acyclovir does not reduce complication rate or contagiousness. Klassen T, et al. The Cochrane Collaboration 2005

8. Acyclovir for chickenpox: when ? • AAP recommends (1993): • Children > 12 years old • Chronic pulmonary/cutaneous conditions • Receiving long-term salicylate therapy • Receiving short, intermittent or aerosolized steroids • Secondary household cases

9. Anti-virals for chickenpoxCONCLUSIONS • Varicella in normal host oral acyclovir • Immunocompromised patients have high incidence of complications and viral resistance: • IV acyclovir • IV foscarnet if resistance suspected • P.O. valacyclovir, famciclovir in small studies but not as yet approved for chickenpox.

10. Acyclovir for chickenpox  doses • Immunocompetent children • P.O.: 80mg/kg/day QID for 5 days • I.V.: 30mg/kg/day or 1500mg/m2/day TID for 710 days • Immunocompetent adults • P.O.: 800 mg x5 times/day for 5 days • Immunocompromised children • P.O.: 250-600mg/m2/dose 45 times/day • I.V.: same as in immunocompetent children • Immunocompromised adults • I.V.:1500mg/m2/day TID for 710 days

11. Herpes Zoster in the US • 10%25% chance of a healthy person developing herpes zoster during a lifetime • About 600,000 cases annually • 1.34.8 cases per 1000 population annually • Risk factors: advancing age, malignacy, immunodeficiency. 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.

12. 25-34 35-44 45-54 55-64 65-74 75 14 15-24 Herpes Zoster: Incidence increases with advancing age 500 Females Males 400 300 Incidence/100,000 Persons/Year 200 100 0 Age (years) International Herpes Management Forum. PPS Europe Ltd; 1993:4.

13. Herpes Zoster: definitions of pain Rashhealed Painresolves Onsetof rash Acute-phase pain Postherpetic neuralgia (PHN) Zoster-associated pain (ZAP)

14. HERPES ZOSTER: WHO TO TREAT?(Within 72 hours from onset) • Not recommended for healthy children. • Immunocompetent adults with zoster ophthalmicus or (+)risk factors for PHN: • Advanced age • Severe pain • Severe rash • Adverse psychological factors • ALL adults ??? • All immunocompromised patients.

15. O O N N HN NH NH N H N N N 2 CH HO N NH 2 O 2 2 O CH(CH CH OCH CH OC ) C 2 2 2 CH CH 3 2 2 2 H Valaciclovir Acyclovir N NH O N NH N N 2 CH 2 CH CH C-O-CH 2 2 3 2 C CH 2 2 CH 2 H O 2 H 2 O CH C H 3 Penciclovir Famciclovir Antiviral therapy:nucleoside analogs Brivudin

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

17. FAMCICLOVIR (Famvir) • Converted to penciclovir. • Bioavailability 77%. • Dosage:250500mg X3/day x7 days • Acyclovir resistant mutants also resistant to penciclovir. • Not approved for children. • The efficacy of famciclovir has not been established for the treatment of herpes zoster in immunocompromised patients.

18. Herpes Zoster:Famciclovir 500 mg TID vs Placebo Time to Loss of PHN 180 FCV 500 mg TID Placebo 163 160 140 119 120 100 Median Days to Loss of PHN 80 63 63 60 40 20 0 Patients 50 Years P=.004 All Patients P=.02 Famciclovir 500 mg TID significantly reduced the duration of PHN by a median of 100 days in patients 50 years Tyring S, et al. Ann Intern Med. 1995;123:89-96..

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

20. BRIVUDIN • Rapid absorption, not affected by food • Bioavailability  30%  Long half-life • Elimination mainly by renal route (65%) • No nephrotoxicity • Administered: 125 mg once daily • Best compliance

22. Anti-virals for herpes zoster(Within 72 hours from onset) • Immunocompetent adults (P.O.): • Acyclovir: 800mg x 5 x 7 days • Valciclovir: 1gm x 3 x 7 days • Famciclovir: 250-500mg x 3 x 7 days • Brivudin: 125mg x 1 x 7 days • Immunocompromised patients: • IV Acyclovir: 1500mg/m2/day TID 7-10d • PO antivirals ????

23. Anti-virals for HZ

24. Chickenpox in normal hosts at high risk for complications. Herpes zoster in adults. Immunocompromised children and adults. Postexposure prophylaxis only in immunocompromised +/- VZIG. All healthy children. Post-exposure prophylaxis in sensitive children and adults. Immune adults? (reduction of HZ). Before organ transplantation? VZV INFECTIONANTIVIRALS VERSUS VACCINATION