HSV-2 = 50% - IMEA

Epidémiologie de l ’infection à HSV2

Estimated Prevalence of STDs in the US
1 Million New Genital Herpes Infections per Year in the US
HPV
20 million
Chlamydia
3 million
Hepatitis B
1.25 million
HIV
1.2 million
Genital Herpes
50 million
1 in Every 5 adult Americans are Infected with Genital Herpes
References:
Centers for Disease Control and Prevention Web site. Available at: www.cdc.gov. Accessed August 10, 2006.
Xu F et al. JAMA. 2006;296:964-973.
U.S. Census Bureau Web site. Available at: http://www.census.gov.

U.S.A.
• NHANES II 76-80 16.4%
• NHANES III 88-94 21.9%
Augmentation de la séroprévalence de 30%
France
• HERPIMAX
– 4412 sérums recueillis en 1996, population générale
– femmes > 35 ans, hommes > 45 ans
femmes 17.9%
Séroprévalence globale 17.2%
hommes 13.7%
Johnson RE New Engl J Med. 1989
Fleming DT. New Engl J Med. 1997
Malkin JE. 39th Iccac San Francisco. 1999

Rachna Gupta, Terri Warren, Anna Wald. Genital Herpes. Lancet Infectious Diseases, 2007, 370, 2127-2136

Epidémiologie de l’infection à HSV-2
en Afrique subsaharienne
• Etudes séro-épidémiologiques
– Devenues possibles gâce à la sérologie spécifique de type
– Ouganda, Tanzanie, Zimbabwe, Afrique du Sud
– Forte prévalence chez les jeunes :
• Moins de 20 ans : 20-30%
• Adultes jeunes : 60-80%
• Femmes plus infectées que les hommes
• Etiologies des ulcérations génitales (2001)
– HSV-2 > Chancre mou > Syphilis
• Excrétion génitale asymptomatique
– Très peu de données
– Femmes enceintes VIH+ au Kenya : 17% de portage cervical
(Mostad et al. J Infect Dis 2000;181:58-63)

• Genital shedding of herpes simplex virus
type 2 in childbearing-age and pregnant
women living in Gabon
Ozouaki F et al. Int J of STD & AIDS,2005

• 355 subjects recruited
– blood and cervicovaginal samples collected
• HSV2 seroprevalence : 65.9% increasing
with age (peak within the range 35-39 y)
• Prevalence of HSV2 DNA genital shedding
was 13.8% on a single sampling episode

• This high prevalence of HSV 2 shedding may be
associated with high risk of HSV 2 vertical
transmission to neonates
• Which in Africa may be higher than that observed
in developed world due to :
– high incidence of HSV2 infection
– high fertility rates in African
– high HIV prevalence young women

Cotonou
HIV-1: 2.8% W, 2.8% M
HSV-2: 30% W, 12% M
Yaounde
HIV-1: 7% W, 3.6% M
HSV-2: 51% W, 27% M
Kisumu
HIV-1: 29% W, 18% M
HSV-2: 68% W 35% M
Ndola
HIV-1: 32% W, 24% M
HSV-2: 55% W, 36% M

Données séro épidémiologiques
Grande variabilité géographique
• Europe de l ’Ouest : 5 - 15%
• U.S.A. : 20%
• Afrique : 30 - 80%

Facteurs de risques
• Age
• Sexe féminin
• Facteurs ajustés sur l ’âge
– Nombre de partenaires sexuels
– Age du premier rapport sexuel
– Antécédents de MST
– Niveau socio-économique faible
Malkin JE. 38th ICCAC San Diego. 1998
Fleming DT. New Engl J Med. 1997
Wald A. Sex Transm Dis. 1997

Transmission
• 144 couples sérodifférents HSV2
– Taux annuel de transmission : 10%
– 70% des cas de transmission survenus alors que le sujet
source était asymptomatique
– Différence liée au sexe
• femme homme : 4.5%
• homme femme : 19%
• Suivi d ’une cohorte de 7046 femmes enceintes
– Taux d ’acquisition de 33% pour HSV2 (4% pour HSV1)
Mertz GJ. Ann Intern Med. 1992
Brown ZA. N Engl J Med. 1997

• Transmission of Herpes Simplex Virus type 2
among factory workers in Ethiopa
Yenew Kebede et al. J of Infect Dis. 2004;190:365-372

• Retrospective study 1997-2002
• 1612 subjects (including 133 heterosexual
couples)
• HSV2 seroprevalence at enrollment : 40.9%
(female : 59.5 – male: 34.6) ; 43.4% 20-30 y

• 41 monogamous HSV2 serodiscordant couples
– 12 with man HSV2 +
– 29 with woman HSV2 +
• HSV2 seroincidence was:
– 20.7 seroconversions /100 PY in women
– 4.9 seroconversions /100 PY in men

• Majority of HSV2 + subjects did not report any
episode of genital ulcer (>90%)
– symptoms are unnoticed and/or
underreported
– probable reason of the widespread dissemination of
HSV2 infection

• Increasing relative prevalence of HSV2
infection among men with genital ulcers
from a mining community in South Africa
Lai W et al. Sex Transm Infect. 2003;79:202-207

• HSV2 as a cause of GUD increased from
17.2% to 36% between 1994 and 1998

Increasing role in HIV susceptibility attributed to HSV-2
(c): Etiology of GUD (%)
South Afr 94
South Afr. 00
Tanzania
T pallidum
30
16.2
15
H ducreyi
12
24.5
10
HSV
9
29.2
45
TP + HD
8
1.7
TP + HSV
1
1.1
HD + HSV
4.8
All 3 agents
0.7
Mixed no HSV
2
LGV
3
C. granulom.
9
2
Indeterm.
23
21.7
HIV Serop.
40
Vanmali et al. ICAAC, 2001/ Chen et al
2000/O'Farell, 1994

Etiology of GUD in South Africa
(1986-98)
Chen CY, Ballard RC et al. Sex Transm Dis. 2000;27:21-29

Herpès génital chez des malades africains
souffrant d’ulcération génitale : Evolution 1980-1999
Pourcentage de HSV-2 isolé
45
40
35
30
25
20
15
10
5
0
1980-84 1985-89 1990-94 1995-99
Harare
Durban-1
Durban-2
Afrique du Sud
Rwanda
Kenya
D’après O’Farrell STI 1999

Rachna Gupta, Terri Warren, Anna Wald. Genital Herpes. Lancet Infectious Diseases, 2007, 370, 2127-2136

Primo infection
Asymptomatique
Symptomatique
Latence
Réponse immunitaire
cellulaire et humorale
Stimuli endo/exogènes
Réactivation
Asymptomatique Subclinique Symptomatique

Excrétion virale
Contact
cutanéo-muqueux
Transmission
Epidémiologie
HSV
Facteurs Géographie Facteurs
comportementaux
socio-économiques

Asymptomatiques
vrais
Symptomatiques
diagnostiqués
20%
20%
60%
Symptomatiques
non diagnostiqués
CoreyL. Sex Transm Dis. 1994

Jean-Elie
Malkin, , Cours IST, IMEA

Jean-Elie
Malkin, , Cours IST, IMEA

Jean-Elie
Malkin, , Cours IST, IMEA

Jean-Elie
Malkin, , Cours IST, IMEA

Jean-Elie
Malkin, , Cours IST, IMEA

Bruno Halioua, , Institut Alfred Fournier

Bruno Halioua, , Institut Alfred Fournier

Diagnostic
Direct
Indirect
mise en évidence du virus
par prélèvement du liquide contenu
dans les vésicules ou érosions fraîches
< 3 jours
•Culture
•Détection des antigènes
•PCR
détection des anticorps
dirigés contre le virus
par prise de sang
•Sérologie

Diagnostic direct :
la culture
C’est la technique de référence
Résultats en 1 à 5 jours
Spécificité +++

Diagnostic indirect : La sérologie
Renseigne sur l’état d’immunité du sujet vis-à-vis
de l ’HSV
De nombreux tests sont disponibles (Elisa ++)
Possibilité de tests spécifiques de type (trousses)
Est utile principalement pour les études épidémiologiques
Grand progrès dans la sensibilité mais encore des faux
négatifs (près de 5 %)
Dans le diagnostic intérêt pour documenter une
primo-infection

Increasing role in HIV susceptibility attributed
to HSV-2 (a)
• 31 studies of HSV-2 seropositive have RR=2.1
of HIV infection when herpes precedes HIV
• Among HSV-2 sero + persons, 52% of ST HIV
infection attributed to HSV
• Population attributable risk % varies with HSV
seroprevalence: 19% for the ST-HIV infection in
the general pop (HSV seroprev=22%) and 50%
for ST HIV in CSWs (HSV seroprev=80%)
Wad. A et al. J Infect Dis, 2002, 185, 45-52)

Wald A. JID: 2002;185:45-52
HSV-2 and HIV acquisition
meta-analysis:
Risk of HIV infection
in HSV-2 infected
persons:
A: 9 Longitudinal &
nested case-control
studies:
RR=2.1 (1.4-3.2)
B: 22 Case-control &
cross sectional
studies:
OR=3.9 (3.1-5.1)

Synergistic Link Between HIV and HSV-2
• HSV-2 increases risk of acquiring HIV by
approximately 3-fold 1
– mucosal barrier breakage may increase susceptibility
to HIV 2
– HSV-2 results in an influx of activated CD4 + T cells
and macrophages into genital mucosa and skin 3
– HIV viral replication is increased by HSV-2 reactivation
and/or shedding 4,5
• HIV can worsen the clinical and subclinical
manifestations of HSV-2 6-8
1. Freeman EE, et al. AIDS. 2006;20:73-83. 5. Schacker T, et al. J Infect Dis. 2002;186:1718-1725.
2. Weiss H. Herpes. 2004;11(suppl 1):24A-35A. 6. Schacker T, et al. J Infect Dis. 1998;178:1616-1622.
3. Koelle DM, et al. J Infect Dis. 1994;169:956-961. 7. Corey L, et al. J Acquir Immune Defic Syndr. 2004;35:435-445.
4. Mole L, et al. J Infect Dis. 1997;176:766-770. 8. Posavad CM, et al. J Infect Dis. 2004;190:693-696.

The Majority of HIV+ Patients Are
Infected With HSV-2
HIV + Population
>1 Million Patients 1
• 60%-70% of HIV +
patients in the
US are also
HIV and HSV-2
HIV only
infected with
HSV-2 2,3
1. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov. Accessed November 14, 2006.
2. Meyer JL, et al. Sex Transm Infect. 2005;81:309-315.
3. Hook EW, et al. J Infect Dis. 1992;165:251-255.

Model Suggests a Significant Proportion of
HIV in the US May Be Attributed to HSV-2 *
• Among HSV-2-seropositive persons, an estimated 52% of sexually
transmitted HIV-1 infections may be attributed to HSV-2 infections
MSM (HSV-2 = 50%)
†
35%
African Americans
(HSV-2 = 50%) †
35%
US Overall
Population
(HSV-2 = 22%) †
19%
HIV Infections Attributable
to HSV-2
Wald A and Link K. J Infect Dis. 2002;185:45-52.
0 10 20 30 40 50 60 70 80 90 100
%
MSM = men who have sex with men
* Population attributable risk is a calculated value
†
The numbers in parentheses refer to the proportion of the specified population that is HSV-2 seropositive

D Serwadda, M Wawer, R Gray, N Swandambo, Population-based research on a very clever virus. CROI, Febr 2008

Ronald Gray, M.D. Reducing HIV transmission: Lessons Reducing HIV transmission: Lessons from Rakai and other
African from Rakai and other African studies. IAS, Rio de Janeiro, 2005

D Serwadda, M Wawer, R Gray, N Swandambo, Population-based research on a very clever virus. CROI, Febr 2008

Marie Laga, The synergy between Prevention and Care in Africa. IAS, Rio de Janeiro, 2005

Elevated Rates of HSV-2 Shedding * Persist
in HIV + Patients Treated With HAART
40
30
20
10
0
15
10
Days of Mucosal HSV Shedding
(median %)
18
HAART-Treated
29
Untreated
Days With HSV Lesions (median %)
11.3
P=0.08
P=0.001
• 28 HAART-treated and 49
untreated subjects with HIV
and HSV-2 evaluated to
determine number of days
with shedding and lesions
• No significant difference on
HAART for shedding or HSV
DNA level
• Significantly fewer days with
HSV lesions on HAART
5
0
2.8
HAART-Treated
Untreated
Posavad CM, et al. J Infect Dis. 2004;190:693-696.

12
10
8
Asymptomatic* HSV-2 Shedding Is
Common Among HIV + Patients †
Percent of Days With Shedding
9.7%
80
70
60
50
Percent of Shedding Days That
Were Asymptomatic
68%
6
4
3.1%
40
30
20
33%
2
10
0
Neg
HIV MSM
Pos
HIV MSM
0
HIV − MSM
HIV + MSM
(n=13)
(n=68)
(n=13)
(n=68)
*Shedding in the absence of lesions. The clinical significance of HSV-2 shedding is unknown
†
Data from patients not receiving HAART; based on results of HSV-2 viral culture
Schacker T, et al. J Infect Dis. 1998;178:1616-1622.
MSM = men who have sex with men

le
meilleur
…de CROI 2008
Un traitement par aciclovir chez des sujets VIH-,
HSV-2+ ne diminue pas le risque d'infection par le VIH
7
Traitement anti-HSV-2 à visée
de prévention du VIH
Aciclovir
400 mg bid
n = 1 637
Femmes VIH- HSV-2+
hétérosexuelles
et
Hommes
Homosexuels
VIH- HSV-2+
Randomisation
Placebo bid
n = 1 640
Critère de jugement principal :
acquisition du VIH
Survie sans VIH
1,0
0,9
0,8
0,7
0,6
0,5
0
Temps avant infection à VIH
3
6
Placebo
Aciclovir
9
Mois
12
p = 0,39
15
18
Celum C, CROI 2008, Abs. 32LB

Connie Celum, HPTN III randomized, placebo control trial of acyclovir for reduction of HIV acquisition among high risk HSV 2 seropositive HIV neg persons, CROI, Febr 2008

Connie Celum, HPTN III randomized, placebo control trial of acyclovir for reduction of HIV acquisition among high risk HSV 2 seropositive HIV neg persons, CROI, Febr 2008

Connie Celum, HPTN III randomized, placebo control trial of acyclovir for reduction of HIV acquisition among high risk HSV 2 seropositive HIV neg persons, CROI, Febr 2008

Connie Celum, HPTN III randomized, placebo control trial of acyclovir for reduction of HIV acquisition among high risk HSV 2 seropositive HIV neg persons, CROI, Febr 2008

HERPES GENITAL
First Clinical Episode
Acyclovir 400 mg orally three times a day for 7--10 days,
OR
Acyclovir 200 mg orally five times a day for 7--10 days,
OR
Famciclovir 250 mg orally three times a day for 7--10
days,
OR
Valacyclovir 1 g orally twice a day for 7--10 days.
(CDC, 2006,WHO, 2004)

HERPES GENITAL
Episodic Therapy for Recurrent
Herpes
Acyclovir 400 mg orally three times a day for 5 days*,
OR
Acyclovir 200 mg orally five times a day for 5 days*,
OR
Acyclovir 800 mg orally twice a day for 5 days*,
OR
Famciclovir 125 mg orally twice a day for 5 days*,
OR
Valacyclovir 500 mg orally twice a day for 3--5 days*,
OR
Valacyclovir 1.0 g orally once a day for 5 days*.
(5-10 days if HIV+, CDC)
(CDC, 2006,WHO, 2004)

HERPES GENITAL
Suppressive Therapy for
Recurrent Herpes
Acyclovir 400 mg orally twice a day,
OR
Famciclovir 250 mg orally twice a day,
OR
Valacyclovir 500 mg orally once a day,
OR
Valacyclovir 1.0 gram orally once a day.
(CDC, 2006,WHO, 2004)

HERPES GENITAL
Suppressive Therapy for
Recurrent Herpes if HIV+
Acyclovir 400--800 mg orally twice to three times a day,
OR
Famciclovir 500 mg orally twice a day,
OR
Valacyclovir 500 mg orally twice a day.
(CDC, 2006)

Suppressive treatment of recurrent genital
herpes
A meta-analysis
(Lebrun-Vignes B, Bouzamoundo A, Dupuy A,
Guillaume JC, Lechat Ph, Chosidow O)
‣Immunocompetent patients, suppressive
treatment of recurrent genital herpes, RCTs vs PBO
‣ 14 RCTs (6158 patients)

Global analysis