herpès génital actualités épidémiologiques et thérapeutiques dr. jean-elie malkin centre...
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Herpès génital
Actualités épidémiologiques et thérapeutiques
Dr. Jean-Elie Malkin
Centre Médical de l’Institut Pasteur
Esther
Primo infection
Asymptomatique Symptomatique
Latence
Réponse immunitaire Stimuli endo/exogènes
cellulaire et humorale
Réactivation
Asymptomatique Subclinique Symptomatique
Excrétion virale
Contact
cutanéo-muqueux
Transmission
Facteurs Géographie Facteurs
comportementaux socio-économiques
EpidémiologieHSV
Direct mise en évidence du virus
par prélèvement du liquide contenu dans les vésicules ou érosions fraîches
< 3 jours
•Culture•Détection des antigènes•PCR
Diagnostic
Indirect
•Sérologie
détection des anticorps dirigés contre le virus
par prise de sang
la culture
Diagnostic direct :
C’est la technique de référence
Résultats en 1 à 5 jours
Spécificité +++
Renseigne sur l’état d’immunité du sujet vis-à-visde 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
Diagnostic indirect : La sérologie
Epidémiologie de l ’infection à HSV2
CoreyL. Sex Transm Dis. 1994
Symptomatiques non diagnostiques
Asymptomatiques vrais
Symptomatiques diagnostiques
20%20%
60%
Données séro épidémiologiques
Grande variabilité géographique
• Europe de l ’Ouest : 5 - 15%• U.S.A. : 20%• Afrique : 30 - 80%
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
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)
Ndola
HIV-1: 32% W, 24% M
HSV-2: 55% W, 36% 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
Cotonou
HIV-1: 2.8% W, 2.8% M
HSV-2: 30% W, 12% M
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
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
1980-1999P
ou
rcen
tag
e d
e H
SV
-2
isolé
0
5
10
15
20
25
30
35
40
45
1980-84 1985-89 1990-94 1995-99
HarareDurban-1Durban-2Afrique du SudRwandaKenya
D’après O’Farrell STI 1999
• 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
Treatment of genital herpesold trends revisited and new directions
Treatment of primary genital herpes (primo-infection or primo-
manifestation)ACV> 10 RCTs vs PBO:
Viral shedding: 7 daysPain: 1-5 daysHealing: 3-10 days
Dosage200 mg x 5 per day or 5 mg/kg/8hrs, 7-10 daysSimilar efficacy of oral and IV ACV (valaciclovir 500
mg or 1000 mg bid could also be used if oral therapy is appropriate)
Episodic treatment of recurrent genital herpes
oral ACV 6 RCTs vs PBO: mild effect-size
Viral shedding: 1-2 daysPain: no effectHealing: 1-2 days
Other limitationsTo be administered as early as possible (should be
patient-initiated as for the other antiviral drugs)Dosage: 5 times per day for 5 days
Episodic treatment of recurrent genital herpes
VACV 500 mg bid is equivalent to ACV 200 mg 5 times daily, 5 days FCV 125 mg bid is equivalent to ACV 200 mg 5 times daily, 5 daysACV 800 mg tid, 2 days, may be usedA 3-day course of VACV 500 mg bid is equivalent to the 5-day course of VACV
Bodsworth N et al. Genitourin Med 1997;73:110-6Chosidow O et al. BJD 2001;144:818-24Wald A et al. CID 2004;34:944-8Leone PA et al. CID 2004;34:958-62
Suppressive treatment of recurrent genital herpes
Daily use of an antiviral drug in order to suppress or delay time to recurrence
In patients with at least 6 recurrences/year
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
Once-daily VACV to reduce the risk
of transmission of genital herpes(Corey L et al. NEJM 2004;350:11-20)
. IC, heterosexual, monogamous couples: one with clinically symptomatic genital HSV-2 and one susceptible (n =1484)
. Partner HSV-2 + randomly assigned to VACV 500 mg OD or PBO for 8 months
. Acquisition of HSV-2: HR = 0.52 (95%CI = 0.27-0.99) (decrease in clinically symptomatic HSV-2 infection)
. Decrease in viral shedding (33%)
Interactions HSV2 / HIV
“The herpetic connection”
Genital Herpes: Early AIDS-associated Opportunistic Infection
acquisition du HIV• HSV2
transmission du HIV
• Mécanismes– Rupture de la barrière épithéliale
– Afflux de cellules cibles au niveau de la lésion
HSV2 cofacteur de transmission en cas de UG
• Nairobi : cohorte de prostituées présentant une UG– 34% PCR (+) HIV DNA– Sur 31 prélèvements PCR (+) HSV2 DNA :
22% PCR (+) HIV DNA
• U.S.A. : 12 homosexuels HSV2 (+) HIV (+)– 25 poussées/26 PCR (+) HIV DNA
Kreiss JK. J Infect Dis. 1989
Schacker T. JAMA. 1998
HSV2 cofacteur de transmission en cas d ’excrétion asymptomatique
• Bangui : étude cas-témoins chez des femmes coinfectées HSV2-HIV– Corrélation significative entre HSV2 DNA et
HIV DNA au niveau des sécrétions cervico-vaginales en dehors de toute poussée
Mbopi-KéouFX. J Infect Dis. 2000
HSV-2 and HIV acquisition
meta-analysis:
Wald A. JID: 2002;185:45-52
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)
• The Impact of Incident and Prevalent Herpes Simplex Virus-2 Infection on the incidence of HIV-1 Infection Among Commercial Sex Workers in South Africa
Ramjee G. et al. J Acquir Immune Defic Syndr. 2005:39(3)
• 416 women screened :
– 50% HIV +
– 84% HSV2 +
• 187 HIV negative women followed up monthly (median duration 2.2 years)
• When HSV2 seroconversion was analysed as a time-dependant covariate, the RR for HIV seroconversion was 6.0 times greater among women with incident that among women with prevalent HSV2 infection
2 types d’essais d’intervention thérapeutique en cours
• 1 : Effet d’un traitement antiherpétique (épisodique et suppressif) chez les coinfectés HSV2/HIV sur la baisse de l’infectivité
• 2 : Effet d’un traitement suppressif chez les sujets HSV2 + sur l’incidence de l’infection HIV
ESSAI ANRS 12-12 (Ghana et République Centrafricaine)
• WAPTCAS, Ghana
• CNRMST & FACSS, RCA
• Inserm U430, HEGP, Paris, FRANCE
• LSHTM, London, UK
• University of Sherbrooke, Canada
• Sponsors: ANRS (France,)
Groupe de travail AC 12 “Microbicides et Prévention de la Transmission Sexuelle du VIH” Groupe de travail AC 12 “Microbicides et Prévention de la Transmission Sexuelle du VIH” Paris, le 4 mars 2005Paris, le 4 mars 2005
24/05/06 - AC12 Paris 55
Syndromic Mx+ Placebo
D2 D4 D7 D14 D28
Outcomes* HIV-1 RNA Lesional, genital and plasma HSV-2 DNALesional and genitalUlcer aetiologiesUlcer healing
Randomisation
Syndromic Mx + Acyclovir
D0
Acrra/KumasiBangui
Study Design
Multicentre, randomised, double-blind placebo-controlled trial
ACV 400 mg x 3/d - 5 days
Ciprofloxacin + Benzathine penicillin 2.4 MU
* LeGoff J et al, J Clin Microbiol 2006;44: 423-32
24/05/06 - AC12 Paris 56
Resultsat
Baseline
24/05/06 - AC12 Paris 57
Population characteristics
• 441 women randomized– HIV-1 seropositive 47% Median CD4+=270; IQR=127-570
– HSV-2 seropositive 79%– HIV-1/ HSV-2 sero+ 41%
0
20
40
60
80
100
HIV-1 prevalence HSV-2 prevalence
HIV+ HIV- HSV2+ HSV2-
P<0.01 P<0.001
10%
57%
96%
64%
0
20
40
60
80
100
24/05/06 - AC12 Paris 58
Ulcer aetiologies(N=422/441)
• HSV-2 in 211 = 50.0%– 1 co-infected with H. ducreyi and 3 with C trachomatis (not
LGV strains)
• H. ducreyi alone in 2 samples = 0.5%• 209 unknown aetiologies = 49.5%• Ulcer swabs were found also positive
– CMV alone in 4 samples = 1.0%– EBV alone in 24 samples = 4.5%– CMV+EBV in 5 samples = 1.2%
24/05/06 - AC12 Paris 59
Genital HSV-2 shedding
• 388/407 CVL without semen contamination– Genital HSV-2 DNA
• Ulcer +/- CVL= 202 (Ulcer = 188; Ulcer + CVL = 131; CVL only = 14)
• Primary Genital Herpes (HSV-2 seroneg) = 24
0
Freq HSV-2 shedding
HIV+ HIV-
Mean CVL HSV-2 DNA
HIV+ HIV-N=184 N=204 N=98 N=47
log 10
cop
ies/
ml
20
40
60
80
100%P<0.001
54%23%
0
1
2
3
4
5
6
3.85 4.13
NS
Genital HSV-2 shedding occured more frequently among HIV-1 + women
24/05/06 - AC12 Paris 60
Genital HIV-1 shedding in HIV-1/HSV-2 co-infected women
% HIV-1 RNA in CVL Median CV HIV-1 RNA (log10 copies/mL)
HSV-2 DNA
N=109 N=71
20
40
60
80
100P=0.001
68% 42%1
2
3
4
5
6P=0.003
3.14 2.1
0 0NegativePositive NegativePositive
Genital HIV-1 shedding among women shedding HSV-2:Occured more frequentlyAssociated with higher viral loads
1 log10 CV HSV-2 DNA 2-fold CV HIV-1 RNA
24/05/06 - AC12 Paris 61
ResultsImpact Study
24/05/06 - AC12 Paris 62
Enrolment, follow-up, complianceEnrolment, follow-up, compliance
490 women presented
449 eligible
441 randomized
220 Placebo arm 221 ACV arm
Mean compliance rate (pill count) = 99% in both arms
Side effects = 8/441 (2%, severity 1 or 2)
54 HIV+ with HSV2 ulcer
52 analysed on day 7 (81%)
42 analysed on day 7 (78%)
64 HIV+ with HSV2 ulcer
Primary analysis group:
118 HIV+ women with HSV-2 ulcer
24/05/06 - AC12 Paris 63
Participants characteristics in Participants characteristics in primary analysis primary analysis groupgroup (HIV+ women with HSV-2 ulcers) (HIV+ women with HSV-2 ulcers) (N=118)(N=118)
4.76 (4.3-5.1)4.63 (4.1-4.9)Mean plasma HIV-1 RNA (CI)
6%5%NG/CT/TV
11%8%Taking HAART
47%42%Experienced GUD last year
3%3%Serological syphilis TPHA/RPR+
194 (92-548)188 (72-519)Median CD4 count (/µL) (IQR)
30.831.4Mean age in years
SM+ACV(n=54)
SM+Placebo(n=64)
24/05/06 - AC12 Paris 64
Impact of ACV on HIV-1 RNA at day 7Impact of ACV on HIV-1 RNA at day 7
67 65
81
69
0
10
20
30
40
50
60
70
80
90
D0 D7
SM+Placebo
SM+ACV
%RR*=0.97 (0.8 - 1.2)
* Adjusted for baseline CV HIV-1 RNA
Cervico-vaginal detection
Cervico-vaginal and plasma HIV-1 RNA loads– No impact on mean cervico-vaginal HIV-1 RNA at day 7 among
shedders (-0.06 log10 copies/mL, P=0.69)– No impact on mean plasma HIV-1 RNA at day 14 (0.02 log10
copies/mL, P=0.89)
24/05/06 - AC12 Paris 65
Impact of ACV on HSV-2 shedding Impact of ACV on HSV-2 shedding at day 7at day 7
• Reduction from: – 81% at D0 to 26% at day 7 in acyclovir arm,– 81% at D0 to 35% at day 7 in placebo arm
=> RR=0.74 (P=0.35)
• Mean quantity HSV-2 DNA was 1.12 log10 copies/mL lower in acyclovir arm than placebo arm (P=0.005)
24/05/06 - AC12 Paris 66
Impact on ulcer healing at day 7 in HIV+ Impact on ulcer healing at day 7 in HIV+ women with HSV-2 ulcerswomen with HSV-2 ulcers
0.03RR=1.6058%42%0%10%% with ulcers <10 mm2
0.25
P- value
RR=1.26% ulcers with >90% size reduction*
55%44%
ACVACV Plac.
D7
Plac.
D0Magnitude
* Excluding ulcers size <10 mm2 at baseline
24/05/06 - AC12 Paris 67
• First results from a large cohort of women with symptomatic genital herpes in Africa
• HSV-2 the dominant GUD aetiology
– Large % of primary genital herpes
• HSV-2 genital infectiousness of HIV-1
CV HIV-1 RNA
plasma HIV-1 RNA (as Mole JID 1997; Schacker JID 2002)
Importance of HIV testing to be offered to GUD patients
x 2.5> x 10
AsymptomaticShedding
Genital Ulcer
(Baeten JID 2004)
ANRS1212: ConclusionsANRS1212: Conclusions
24/05/06 - AC12 Paris 68
Despite some impact on HSV-2, episodic treatment with ACV has no measurable impact on HIV-1 replication– Too little/too short (5 days)?– Too late? (median 7 days after ulcer first noticed by woman)
– Advanced HIV disease in many women– Delayed impact? Inadequate outcome (D7?), sample size, etc?– Await results of other trials in Malawi and South Africa
– Prevention of HSV-2 reactivations perhaps more effective in controlling HSV and HIV transmissibility
ANRS1212: ConclusionsANRS1212: Conclusions
24/05/06 - AC12 Paris 69
AcknowledgementsAcknowledgements
• CNRMST, Bangui– Gerard Gresenguet, Jean-de-
Dieu Longo• WAPCAS, Ghana
– Thomas Agyarko-Poku, Comfort Asamoah-Adu, Agnes Dzokoto, Khonde Nzambi
• Sherbrooke University, Canada– Sylvie Deslandes, Eric Frost,
Jacques Pepin• HPA, London
– David Brown, John Parry• Institut Pasteur, Paris
– Jean-Elie Malkin
• INSERM U743, Paris– Laurent Belec, Jerome LeGoff,
Hicham Bouhlal, Cecile Chemin, Maxime Lecerf, Ali Si-Mohamed
• LSHTM, London– Richard Hayes, David Mabey,
Philippe Mayaud, Helen Weiss• Scientific Advisors
– Yaw Adu-Sarkodie, Francis Ndowa (WHO), Jamie Robinson (GSK R&D), Simon Cousens, Mike Kenward, David Dunn, Andrew Nunn, Jean-Marie Huraux
• DSMB– Peter Smith (Chair, LSHTM), Tim
Clayton (LSHTM), Anne Johnson (Royal Free)
Nairobi, Eldoret, Kisumu, Kenya
Kampala, Uganda
Moshi, Tanzania
Johannesburg, Durban RSA
Gabarone, Botswana
Kitwe and Ndola, Zambia
Prospective sites for Gates HSV-HIV transmission trial
3646 HIV- discordant couples
Aciclovir 400 mg bid x 1 yr Placebo x 1 yr
Randomize HIV+/HSV2 + persons w/ CD4 > 250
1° endpoint: HIV infection in HIV-negative partners at 1 yr
HSV-2 serology & CD4 testing of HIV+ partner
HSV-2 suppressive therapy to prevent HIV transmission
1800 HIV-/ HSV2+heterosexual women
and
1800 high-risk, HIV-/ HSV2+ MSM
Aciclovir 400 mg bid x 1 yr Placebo x 1 yr
Randomize
Harare, ZimbabweLusaka, ZambiaJohannesburg, SA
Lima, PeruSeattle, USASan Francisco, USANew York, USA
1° endpoint: HIV infection (estimated to be 3.5%/yr in placebo arm)
Proof-of-concept trial of HSV-2 suppressive therapy to prevent
HIV acquisition
• Two double blind, randomized, placebo-controlled trials
• Study 1 (57 centers) randomized 847 both HSV-1 and HSV-2 seronegative partners of HSV-2 infected persons (clinically confirmed genital herpes)
• Study 2 (60 centers) randomized 1867 HSV-2 seronegative partners of HSV-2 infected persons (clinically confirmed genital herpes)
• Vaccinations: 0, 1, and 6 months – I.m. administration
• Follow-up period: 19 months
• Primary efficacy endpoint: Acquisition of genital herpes disease
Glycoprotein-D-adjuvant vaccine to prevent genital herpes
(Stanberry LR et al. NEJM 2002;347:1652-61)
Vaccine Efficacy p-value
73.2% 0.01
Vaccine Efficacy p-value
-10.9% 0.81
Men Women
Pe
rce
nta
ge
with
ou
t G
HD
Observation period [months] Observation period [months]0 2010 30
85
90
95
100
VaccinePlacebo
0 2010 30
VaccinePlacebo
85
90
95
100
STUDY 1- HSV-2 VACCINEGenital Herpes Disease
HSV 1-/2- Subjects
Vaccine Efficacy p-value
32.2% 0.47
Vaccine Efficacy p-value
74.4% 0.02
Observation period [months] Observation period [months]
Pe
rce
nta
ge
with
ou
t G
HD
Men Women
0 2010 30
85
90
95
100
PlaceboVaccine
0 2010 30
85
90
95
100
PlaceboVaccine
STUDY 2- HSV-2 VACCINEGenital Herpes Disease
HSV 1-/2- Subjects
STUDY 2- HSV-2 VACCINEGenital Herpes Disease
HSV 1+/2- Subjects
Observation period [months] Observation period [months]
Pe
rce
nta
ge
with
ou
t G
HD
Men Women
100
PlaceboVaccine
0 2010 30
85
90
95
PlaceboVaccine
0 2010 30
85
90
95
100