““Update and new Update and new perspectives on HSV perspectives on HSV

infectionsinfections””

Paulo R. Cunha, MD, PhD.Professor of Dermatology

Jundiaí Medical SchoolSão Paulo, Brazil

21st World Congress of Dermatology

Oct/2007

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

DNA Virus

  Serological techniques:

HSV-1: glycoprotein gC1 HSV-2: glycoprotein gC2

Capsid

Capsomers

Cell membrane

Cytoplasm Herpes virus

Virus new particle

Keratinocyte

DNA HSV

Cytoplasmic Membrane

Acyclovir

Timidina Kinase (TK)

AcyclovirMonophosphate

AcyclovirTriphosphate

Genital Herpes: CDC Treatment Recommendations

Valacyclovir 1000 bid 500 bid (3†-5 d) 500 qd‡

1000 qd (5 d) 1000 qd

Acyclovir 400 tid 400 tid (5 d) 400 bid 200 5/day800 bid (5 d)

200 5/day (5 d)

Famcyclovir 250 tid* 125 bid (5 d) 250 bid up to 1 year

genital herpesepisode episodic

suppressive(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.

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

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

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

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)

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

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

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

New Antiherpes Vaccines by Genetic Engineering

An ideal vaccine should induce Cellular and Humoral Immune Response adequate to prevent infection.

Vaccines by genetic engineering

Plasmid insertion Plasmid transference

Chromosome

transformed bacteria

PCMV T7His6EK 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 )

Cellular and Humoral Immune Response

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

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

Herpes Virus Vaccine Studies

Prophylactic Vaccines for HSV-2Genetically 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

ConclusionsHSV 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.

Thank you!drpaulocunha@bol.com.br