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. Common, highly contagious but usually mild disease of childhood. Complications in 5-10 %. Complications in 5-10 %. Hospitalization rate 8-10/10 4 children, highest in children <4 years old. Hospitalization rate 8-10/10 4 children, highest in children <4 years old. Increased incidence of complications in neonates, adolescents, adults and immunocompromised patients. 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. 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. 1992:FDA approved oral acyclovir for tx of chickenpox in normal children.

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

7. Klassen T, et al. The Cochrane Collaboration 2005 Acyclovir for treating varicella in normal children Did not significantly reduce: Did not significantly reduce: 1. Days to new lesions 2. Days to relief of itching Moreover acyclovir does not reduce complication rate or contagiousness. Moreover acyclovir does not reduce complication rate or contagiousness.

8. Acyclovir for chickenpox: when ? AAP recommends (1993): AAP recommends (1993): 1.Children > 12 years old 2.Chronic pulmonary/cutaneous conditions 3.Receiving long-term salicylate therapy 4.Receiving short, intermittent or aerosolized steroids 5.Secondary household cases

9. Anti-virals for chickenpox CONCLUSIONS Varicella in normal host oral acyclovir Varicella in normal host oral acyclovir Immunocompromised patients have high incidence of complications and viral resistance: 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 Immunocompetent children  P.O.: 80mg/kg/day QID for 5 days  I.V.: 30mg/kg/day or 1500mg/m 2 /day TID for 710 days  Immunocompetent adults  P.O.: 800 mg x5 times/day for 5 days  Immunocompromised children  P.O.: 250-600mg/m 2 /dose 45 times/day  I.V.: same as in immunocompetent children  Immunocompromised adults  I.V.:1500mg/m 2 /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 10%25% chance of a healthy person developing herpes zoster during a lifetime About 600,000 cases annually About 600,000 cases annually 1.34.8 cases per 1000 population annually 1.34.8 cases per 1000 population annually Risk factors: advancing age, malignacy, immunodeficiency. 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. Herpes Zoster: Incidence increases with advancing age Age (years)  14 15-24 25-3435-4445-5455-6465-74  75 0 100 200 300 400 500 Incidence/100,000 Persons/Year Females Males International Herpes Management Forum. PPS Europe Ltd; 1993:4.

13. Herpes Zoster: definitions of pain Acute-phase painPostherpetic neuralgia (PHN) Onset of rash Rash healed Pain resolves Zoster-associated pain (ZAP)

14. HERPES ZOSTER: WHO TO TREAT? (Within 72 hours from onset) Not recommended for healthy children. Not recommended for healthy children. Immunocompetent adults with zoster ophthalmicus or (+)risk factors for PHN: 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. Antiviral therapy: nucleoside analogs Valaciclovir NH 2 CH(CH 3 ) 2 CH 2 OCH 2 CH 2 OC HN O N H C H 2 N O N N Famciclovir NH 2 CH 2 2 2 3 C 3 C-O-CH 2 O N N N C O O H Acyclovir NH 2 CH 2 2 2 HO O O N N N Penciclovir 2 2 CH 2 2 2 H N H Brivudin

16. 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 patients. Not approved in immunocompromised patients.

17. FAMCICLOVIR (Famvir) Converted to penciclovir. Converted to penciclovir. Bioavailability 77%. Bioavailability 77%. Dosage:250500mg X3/day x7 days Dosage:250500mg X3/day x7 days Acyclovir resistant mutants also resistant to penciclovir. Acyclovir resistant mutants also resistant to penciclovir. Not approved for children. Not approved for children. The efficacy of famciclovir has not been established for the treatment of herpes zoster in immunocompromised patients. 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 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 Median Days to Loss of PHN 180 100 All Patients P=.02 120 80 40 20 160 Patients  50 Years P=.004 FCV 500 mg TID Placebo 63 119 63 163

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

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

22. Anti-virals for herpes zoster (Within 72 hours from onset) Immunocompetent adults (P.O.): 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/m 2 /day TID 7-10d  PO antivirals ????

23. Anti-virals for HZ DrugDoses/day Year approved Cost (euro) Acyclovir (Zovirax) 51980s64.22 Valciclovir (Valtrex) 31995110.96 Famcyclovir (Famvir) 31998 110.94 170.79 Brivudin (Brivir) 12002108.66

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