herpès génital actualités épidémiologiques et thérapeutiques dr. jean-elie malkin centre...

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