2. “ Update and new perspectives on HSV infections ” Paulo R. Cunha, MD, PhD. Professor of Dermatology Jundiaí Medical School São Paulo, Brazil 21st World Congress of Dermatology Oct/2007

3. Introduction Over 70% of the population has been infected by either HSV-1 or HSV-2 Produce: primary, latent and recurrent infections. Clinical manifestation: “benign and malign” Extragenital Herpes: 80-90%: HSV-1 Genital Herpes: (normally sexual transmission) 80-90%: HSV-2

4. DNA Virus Serological techniques: HSV-1: glycoprotein gC1 HSV-2: glycoprotein gC2

5. Capsid Capsomers Cell membrane Cytoplasm Herpes virus Virus new particle Keratinocyte DNA HSV

7. Cytoplasmic Membrane Acyclovir Timidina Kinase (TK) Acyclovir Monophosphate Acyclovir Triphosphate

8. Genital Herpes: CDC Treatment Recommendations Valacyclovir1000 bid 500 bid (3 † -5 d) 500 qd ‡ 1000 qd (5 d) 1000 qd Acyclovir400 tid400 tid (5 d) 400 bid 200 5  /day800 bid (5 d) 200 5  /day (5 d) Famcyclovir250 tid*125 bid (5 d) 250 bid up to 1 year genital herpes episodeepisodicsuppressive (mg for 7–10 days)(mg  days)(mg, daily) *Not FDA approved † New FDA-approved dosing ‡ May be less effective in patients who have very frequent recurrences (  10 episodes/year) First clinical Recurrent genital herpes Centers for Disease Control and Prevention. MMWR. 2002;51(RR-6)12-17.

9. Issues to be considered in Suppressive Therapy Not necessary to wait 6 outbreaks in 12 months Define impact of genital herpes Gravity and duration of the outbreak

10. New Therapeutic Options 1) Analog of nucleoside Cidofovir (gel 0.3 or 1%) Single-dose confers a significant antiviral effect on lesions of recurrent genital herpes. Antimicrob Agents Chemother 1998 Nov;42(11):2996-9

11. New Therapeutic Options 2) Immunomodulator Resiquimod (gel 0.05%) Significant reduction in number of recurrences J Infect Dis 2001 Jul 15;184(2):196-200

12. New Therapeutic Options 3) Fusion Inhibitor Docosanol (Abreva®) (cream 10%) interferes with the process of viral fusion with the host cell. Effective treatment for recurrent HSL. J Am Acad Dermatol 2001 Aug; 45 (2): 222-30)

13. Foscarnet is the choice in pts with HSV resistant to acyclovir. It is effective in destroying the virus timidina kinase lacking (nephrotoxicity). Rio Dermatológico 2001 July/August/September Foscarnet (cream 2%) is an effective and safe medication in the treatment of HSL. Hautarzt. 2006 Jan;57(1):40-6 New Therapeutic Options 4) Direct action in DNA polimerase of HSV

14. New Therapeutic Options 5) Helicase inhbitors Nature Med. 8,392-398, 2002). (Phase III) (Phase III) Could increase the intervals between the crises and it is more effective then acyclovir

15. Avoid: Arginine, “Herpetogenic” foods like chocolate, peas, cola drinks, grain cereals, peanuts, gelatin, cashews, beer. Encourage: Lysine, Foods like dairy products, milk, potatoes, brewer’s yeast. Treatment of Recurrent Herpes Simplex with L-Lysine Decreases recurrence and severity Long-term: L-Lysine 1 g/day

16. New Antiherpes Vaccines by Genetic Engineering An ideal vaccine should induce Cellular and Humoral Immune Response adequate to prevent infection.

17. Vaccines by genetic engineering Plasmid insertion Plasmid transference Chromosome transformed bacteria P CMV T 7 His 6 EK BGH f1 SV40 N SV40 ColE1 Amp pA ori ori pA Vaccines with DNA of plasmid that contains the codes of viral glycoproteins ( pcDNA3.1/His A,B,C 5.5 kb )

18. Cellular and Humoral Immune Response

19. Herpes Virus Vaccine: News and Perspectives The most hopeful result was obtained with HSV-2 gD2 and alum/MPL vaccine (Glaxo SmithKline) in clinical studies. -74% effective in preventing genital disease -Only in women who had never been exposed to HSV previously. -Not effective in men

20. DISC (Disabled Infectious Single Cycle) virus HSV vaccine contains a virus with deletion of an essential gene (gH gene), so the replication has been limited to a single cycle only. Guinea pigs were protected from a primary infection. Significant protection from recurrent disease was also observed. Herpes Virus Vaccine: News and Perspectives

21. Herpes Virus Vaccine Studies Prophylactic Vaccines for HSV-2 Genetically engineered HSV to produce a vaccine that is protective without causing human disease is in development. Using a vaccine with live attenuated HSV from which neurovirulence gene (gamma 1 34.5) has been removed, has debilitated HSV in its ability to establish latency and be reactivated. Animals vaccinated are able to elicit protective immune responses Mikrobiyol Bul. 2006 Oct;40(4):413-33

22. Conclusions HSV Vaccine is still a challenge. Seronegative individuals at high risk for infection represent ideal candidates for vaccine trials. Individuals with frequent recurrences are not significantly responsive to vaccines so far. Promising approaches to engineered HSV vaccines should be possible within the next several years. We are in the right road but we have to keep walking. Sexual education, campaigns of information and the use of preservative continues to be essential.

23. Thank you! drpaulocunha@bol.com.br