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Herpès génital Actualités épidémiologiques et thérapeutiques Dr. Jean-Elie Malkin Centre Médical de lInstitut Pasteur Esther.

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Herpès génital Actualités épidémiologiques et thérapeutiques Dr. Jean-Elie Malkin Centre Médical de lInstitut Pasteur Esther.

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Présentation au sujet: "Herpès génital Actualités épidémiologiques et thérapeutiques Dr. Jean-Elie Malkin Centre Médical de lInstitut Pasteur Esther."— Transcription de la présentation:

1 Herpès génital Actualités épidémiologiques et thérapeutiques Dr. Jean-Elie Malkin Centre Médical de lInstitut Pasteur Esther

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

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11 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

12 la culture Diagnostic direct : Cest la technique de référence Résultats en 1 à 5 jours Spécificité +++

13 Renseigne sur létat dimmunité 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 Diagnostic indirect : La sérologie

14 Epidémiologie de l infection à HSV2

15 CoreyL. Sex Transm Dis. 1994

16 Données séro épidémiologiques Grande variabilité géographique Europe de l Ouest : % U.S.A. : 20% Afrique : %

17 U.S.A. NHANES II % NHANES III % 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 Fleming DT. New Engl J Med Malkin JE. 39th Iccac San Francisco. 1999

18 Epidémiologie de linfection 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)

19 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

20 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 Fleming DT. New Engl J Med Wald A. Sex Transm Dis. 1997

21 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 Brown ZA. N Engl J Med. 1997

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

23 Retrospective study subjects (including 133 heterosexual couples) HSV2 seroprevalence at enrollment : 40.9% (female : 59.5 – male: 34.6) ; 43.4% y

24 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

25 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

26 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:

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

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

29 Herpès génital chez des malades africains souffrant dulcération génitale : Evolution Pourcentage de HSV-2 isolé Daprès OFarrell STI 1999

30 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

31 355 subjects recruited –blood and cervicovaginal samples collected HSV2 seroprevalence : 65.9% increasing with age (peak within the range y) Prevalence of HSV2 DNA genital shedding was 13.8% on a single sampling episode

32 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

33 Treatment of genital herpes old trends revisited and new directions

34 Treatment of primary genital herpes (primo-infection or primo- manifestation) ACV > 10 RCTs vs PBO: Viral shedding: 7 days Pain: 1-5 days Healing: 3-10 days Dosage 200 mg x 5 per day or 5 mg/kg/8hrs, 7-10 days Similar efficacy of oral and IV ACV (valaciclovir 500 mg or 1000 mg bid could also be used if oral therapy is appropriate)

35 Episodic treatment of recurrent genital herpes oral ACV 6 RCTs vs PBO: mild effect-size Viral shedding: 1-2 days Pain: no effect Healing: 1-2 days Other limitations To be administered as early as possible (should be patient-initiated as for the other antiviral drugs) Dosage: 5 times per day for 5 days

36 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 days ACV 800 mg tid, 2 days, may be used A 3-day course of VACV 500 mg bid is equivalent to the 5-day course of VACV Bodsworth N et al. Genitourin Med 1997;73:110-6 Chosidow O et al. BJD 2001;144: Wald A et al. CID 2004;34:944-8 Leone PA et al. CID 2004;34:958-62

37 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

38 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)

39 Global analysis

40 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 = ) (decrease in clinically symptomatic HSV-2 infection). Decrease in viral shedding (33%)

41 Interactions HSV2 / HIV The herpetic connection

42 Genital Herpes: Early AIDS- associated Opportunistic Infection

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44 acquisition du HIV HSV2 transmission du HIV Mécanismes –Rupture de la barrière épithéliale –Afflux de cellules cibles au niveau de la lésion

45 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 Schacker T. JAMA. 1998

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47 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

48 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 ( ) B: 22 Case-control & cross sectional studies: OR=3.9 ( )

49 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)

50 416 women screened : –50% HIV + –84% HSV2 +

51 187 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

52 2 types dessais dintervention thérapeutique en cours 1 : Effet dun traitement antiherpétique (épisodique et suppressif) chez les coinfectés HSV2/HIV sur la baisse de linfectivité 2 : Effet dun traitement suppressif chez les sujets HSV2 + sur lincidence de linfection HIV

53 ESSAI ANRS (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 Paris, le 4 mars 2005

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55 24/05/06 -AC12 Paris55 Syndromic Mx + Placebo D2 D4 D7 D14 D28 Outcomes* HIV-1 RNA Lesional, genital and plasma HSV-2 DNA Lesional and genital Ulcer aetiologies Ulcer healing Randomisation Syndromic Mx + Acyclovir D0 Acrra/Kumasi Bangui 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:

56 24/05/06 -AC12 Paris56 Results at Baseline

57 24/05/06 -AC12 Paris57 Population characteristics 441 women randomized –HIV-1 seropositive 47% Median CD4+=270; IQR= –HSV-2 seropositive 79% –HIV-1/ HSV-2 sero+ 41% HIV-1 prevalence HSV-2 prevalence HIV+HIV- HSV2+HSV2- P<0.01P< % 57% 96% 64%

58 24/05/06 -AC12 Paris58 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%

59 24/05/06 -AC12 Paris59 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=184N=204N=98N=47 log 10 copies/ml % P< % 23% NS Genital HSV-2 shedding occured more frequently among HIV-1 + women

60 24/05/06 -AC12 Paris60 Genital HIV-1 shedding in HIV-1/HSV-2 co-infected women % HIV-1 RNA in CVL Median CV HIV-1 RNA (log 10 copies/mL) HSV-2 DNA N=109N= P= %42% P= NegativePositive NegativePositive Genital HIV-1 shedding among women shedding HSV-2: Occured more frequently Associated with higher viral loads 1 log 10 CV HSV-2 DNA 2-fold CV HIV-1 RNA

61 24/05/06 -AC12 Paris61 Results Impact Study

62 24/05/06 -AC12 Paris62 Enrolment, follow-up, compliance 490 women presented 449 eligible 441 randomized 220 Placebo arm221 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

63 24/05/06 -AC12 Paris63 Participants characteristics in primary analysis group (HIV+ women with HSV-2 ulcers) (N=118) 4.76 ( )4.63 ( ) Mean plasma HIV-1 RNA (CI) 6%5% NG/CT/TV 11%8% Taking HAART 47%42% Experienced GUD last year 3% Serological syphilis TPHA/RPR+ 194 (92-548)188 (72-519) Median CD4 count (/µL) (IQR) Mean age in years SM+ACV (n=54) SM+Placebo (n=64)

64 24/05/06 -AC12 Paris64 Impact of ACV on HIV-1 RNA at day 7 % RR*=0.97 ( ) * 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 log 10 copies/mL, P=0.69) –No impact on mean plasma HIV-1 RNA at day 14 (0.02 log 10 copies/mL, P=0.89)

65 24/05/06 -AC12 Paris65 Impact of ACV on HSV-2 shedding at 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 log 10 copies/mL lower in acyclovir arm than placebo arm (P=0.005)

66 24/05/06 -AC12 Paris66 Impact on ulcer healing at day 7 in HIV+ women with HSV-2 ulcers 0.03RR=1.6058%42%0%10% % with ulcers <10 mm P- value RR=1.26 % ulcers with >90% size reduction* 55%44% ACV Plac. D7 Plac. D0 Magnitude * Excluding ulcers size <10 mm 2 at baseline

67 24/05/06 -AC12 Paris67 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 Asymptomatic Shedding Genital Ulcer (Baeten JID 2004) ANRS1212: Conclusions

68 24/05/06 -AC12 Paris68 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: Conclusions

69 24/05/06 -AC12 Paris69Acknowledgements 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)

70 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

71 3646 HIV- discordant couples Aciclovir 400 mg bid x 1 yrPlacebo 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

72 1800 HIV-/ HSV2+ heterosexual women and 1800 high-risk, HIV-/ HSV2+ MSM Aciclovir 400 mg bid x 1 yrPlacebo x 1 yr Randomize Harare, Zimbabwe Lusaka, Zambia Johannesburg, SA Lima, Peru Seattle, USA San Francisco, USA New 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

73 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: )

74 MenWomen Percentage without GHD Observation period [months] STUDY 1- HSV-2 VACCINE Genital Herpes Disease HSV 1-/2- Subjects

75 Observation period [months] Percentage without GHD MenWomen Placebo Vaccine Placebo Vaccine STUDY 2- HSV-2 VACCINE Genital Herpes Disease HSV 1-/2- Subjects

76 STUDY 2- HSV-2 VACCINE Genital Herpes Disease HSV 1+/2- Subjects Observation period [months] Percentage without GHD MenWomen 100

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