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Transmission sexuelle du VIH et ses cofacteurs

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1 Transmission sexuelle du VIH et ses cofacteurs
Philippe Mayaud Reader in Infectious Diseases & Reproductive Health London School of Hygiene & Tropical Medicine, UK

2 Plan Facteurs contribuant à la transmission sexuelle du VIH
Stratégies pour la prévention de la transmission sexuelle du VIH Elargir le champ à l’utilisation des antirétroviraux

3 Transmission du VIH Sexuelle dans 75% des cas aux USA (CDC, 2004)
>90% dans les PED (Gouws, STI 2006; OMS, 2008) Autres Maternelle Intraveineuse (IDU). Injections Transfusion et autres

4 Dynamique de la transmission sexuelle du VIH et IST: the basic reproductive rate or number (R0)
R0 = c  ß  D Taux d’exposition des parternaires susceptibles a leurs partenaires infectieux Duree de la periode infectieuse Probabilite/coefficient de transmission If R0 > 1, epidemie If R0 < 1, controle

5 Dynamique de la transmission du VIH: (c)
MSM IDUs FSW Low risk males Clients Low risk females Adapted from: T. Brown, UNAIDS Collaborating Centre at the East-West Centre

6 Four Cities Study Prevalence VIH <5% Prevalence VIH 15-30% Kisumu
Cotonou Adult prevalence rate 15.0% – 36.0% 5.0% – 15.0% 1.0% – 5.0% 0.5% – 1.0% 0.1% – 0.5% 0.0% – 0.1% not available Kisumu Yaoundé Ndola FOUR CITIES STUDIES – AIDS 2001 Aim: to examine factors affecting differential spread of HIV infection across Africa Cross-sectional, population-based sample of 2000 adults in four cities Detailed data on socio-demographic, behavioural and biological factors Factors compared between high and low HIV prevalence cities EXPOSURE Lifetime partners Partners in last 12 months Age at first sex Age at marriage Age difference between partners TRANSMISSION PROBABILITY FACTORS Condom use STIs Dry sex Male circumcision HIV-1 subtype AIDS 2001 Volume 15 Suppl. 4

7 Résumé des facteurs influençant
l’épidemiologie différentielle du VIH dans la “4-cities study” HSV-2 Age aux premiers rapports Age au marriage Différence d’age entre époux Absence de circoncision VIH

8 Transmission sexuelle du VIH: Facteurs influençant la transmissibilité (ß)
Défaut d’utilisation des préservatifs Types de rapports sexuels Présence d’autres IST Non circoncision masculine Temps écoulé depuis l’infection primaire et charge virale Types et sous-types viraux ?

9 Transmission du VIH: Facteurs biologiques
Agent infectieux Hôte susceptible Inoculum (concentration) résistance héréditaire Phénotypes résistance innée résistance acquise (immunitaire) Galvin SR & Cohen MS. Nature Rev Microbiol 2004; 2:

10 semen lamina propria dendritic cell exposure CD4+ at mucosal CCR5+
SI HIV (T-tropic) NSI HIV (M-tropic) semen lamina propria dendritic cell CD4+ CCR5+ DC-SIGN+ exposure at mucosal epithelium CD4 DC-SIGN CCR5 T cell migration to lymphoid organs “Hand-Off” of HIV-1 from dc to T cells via DC-SIGN Activation State of T cells? Source: Cohen M

11 Variations dans le risque de transmission
Dépendant de: l’infectiosité du patient séropositif (charge virale) la susceptibilité du partenaire séronégatif (CCR5) le type/sous-type viral? certains cofacteurs peuvent modifier ce risque++

12 Ulcères ↗ risque d’infection VIH M -> F: x 10-50
F -> N: x Hayes RJ, et al. Trop Med Hyg 1995; 98:1-8.

13 Charges Virales Plasmatiques au Malawi: Infection VIH Chronique vs
Charges Virales Plasmatiques au Malawi: Infection VIH Chronique vs. Aigue 10 8 6 Log HIV RNA cp/ml 4 2 VIH Ac+ VIH Ac- / p24 Ag+ (aigue) Adapted from: Pilcher CD, et al. AIDS 2004; 18: 1-8

14 Sexual Transmission of HIV Adapted from: Cohen MS & Hoffman I
Sexual Transmission of HIV Adapted from: Cohen MS & Hoffman I. Lancet 1998; 351: 5-7 Risk of Transmission Reflects Genital Viral Burden 2 3 4 5 1/30- 1/200 HIV RNA in Semen (Log10 copies/ml) 1/100- 1/1000 1/500 - 1/2000 1/1000 - 1/10,000 Acute Infection 3 wks Asymptomatic Infection HIV Progression AIDS

15 Wawer M et al, JID 2005; 191:1403–9

16 Influence de la Charge Virale et des Ulcères HIV-1 transmission probability per sexual intercourse in sero-discordant couples in Rakai, Uganda (Gray RH, et al. Lancet 2001; 357: ) 0.001 0.002 0.003 0.004 0.005 0.006 <1,700 1,700 – 12,500 12,500 – 38,500 > 38,500 Without ulceration With ulceration Plasma HIV-1 load in infected partner (copies/ml) Transmission probability per coital act

17 Rôle potentiel des IST dans la transmission et la progression du VIH
HIV RNA in Semen (Log10 copies/ml) Infection Aigue 3 sem. Episode IST SIDA 2 3 4 5 This is a borrowed diagram from my friend Mike Cohen who uses it to show the transmission probabilities at different stages of the HIV disease and the enhanced transmissibility of HIV when concurrent STI occur; in Red = Genital load and risk of transmission. In Yellow = viral load, which reflects genital load too Mike uses the figure to support the management of STI, and lately has been using it to support the management of acute HIV infection – this may well be effective (to be demonstrated), but in practice it will be difficult to find such patients, particularly in resource poor countries (moreover their ‘heightened infectiousness might be short duration) I will use this nice and simple diagram to show the potential place of HSV therapy at different stages of HIV disease CLICK Unfortunately, as we know, HAART comes late in the course of HIV disease in many LIC; although ARVs might have an impact in reducing HIV transmission at the individual level even at this stage, it remains to be proven that HAART would actually curb transmission at the population level On the other hand, there can be recognisable episodes of STI (or herpes), in this case genital ulcer episodes, which might be treated with episodic therapy (SHOW CENTRE), but above all should alert the clinician for the need of HIV testing; suppressive therapy could be offered from then on (SHOW RIGHT), and might delay the requirement for HAART (and save costs and improve quality of life) – it remains to be decided which strategy should be used and when/with which patients. Of course there is much hope that HSV therapy might also prevent HIV acquisition in the first place (SHOW LEFT) Cohen MS & Pilcher C. JID 2005; 191:1391-3

18 Stratégies de contrôle pour la prévention de la transmission sexuelle du VIH
R0 = c  ß  D Réduire l’exposition (c) Réduire le risque de transmission (ß) Réduire la durée d’infectiosité (D)

19 Stratégies de contrôle pour la prévention de la transmission sexuelle du VIH
Réduire l’exposition (c) Modification des comportements sexuels Préservatifs Conseils et dépistage (VCT) Réduire la durée d’infectiosité (D) Réduire le risque de transmission (ß) R0 = c  ß  D

20 Prévention Primaire (1)
QUOI? IEC: connaissances et attitudes sur: risque de transmission sexuelle, measures préventives, recherches des soins, “sexual health”, problèmes de genre, etc Skills building, counselling méthodes de protection: préservatifs (♂♀), microbicides POUR QUI? ciblant les divers groupes à risque (jeunes, militaires, travailleuses du sexe, chauffeurs routiers)? population générale Peu d’evaluations rigoureuses des programmes (notamment chez les jeunes – cf “Steady, Ready, Go!” OMS 2006)

21 ‘Tabourets’ /‘Seater’ community, Cotonou, Benin

22 Trends in incidence of HIV and other STD among HIV-1 negative FSW in Kinshasa
Laga M, et al. Lancet 1994; 344: 6-monthly HIV-1 incidence rates (per 100 women-years) Gonococcal infection Chlamydial infection Trichomoniasis Genital ulcer disease STD incidence rate per 100 person-months HIV incidence rate per 100 person-years The classical intervention study by Marie Laga and collaborators in Kinshasa, Zaire, consisted of provision of monthly STI screening and treatment, combined with condom promotion to sex workers. The study measured the impact on HIV incidence, incidence and prevalence of other STIs, and reported behaviour change. What can be seen, from this somewhat crowded slide, is that among 531 initially HIV-1 negative women, a steady and significant decline of HIV-1 incidence was observed over time, from 11.7/100 wy during the first 6 months, to 4.4/100 women-years over the last 6 months, 3 years later. The effect was particularly strong among women regularly attending the services Simultaneously, the rate of various STIs decreased (except perhaps Chlamydia), and the regular use of condoms with clients went up from 11% to 52% at 6 months, and 68% after 36 months of intervention, respectively. In this study, for the first time, non-ulcerative STI were found to be risk factors for HIV-1 acquisition, after controlling for sexual exposure. A number of other studies among Sex workers have been able to replicate those results. However, most, if not all, were not randomised controlled trials! Months since start of the study

23 Comparison of HIV incidence among sex workers before and during 2 levels of STI interventions in Abidjan (Côte d’Ivoire) Ghys P, et al. AIDS 2001; 15: 1421

24 Prévention Primaire (2)
Campagne “100% condom use” en Thailande (supportée par l’amélioration de l’accès et de la qualité des soins pour IST)

25 Number of male STI cases & condom use in FSW acts, Thailand (1987-1993)
Hanenberg R, et al. Lancet 1994;3 44:

26 Impact de la campagne “100% Condom Use” en Thailande Celentano DD, et al. AIDS 1998;12:F29-36
Changements des comportements sexuels; augmentation du taux d’utilisation des préservatifs avec les TS Augmentation des ventes de préservatifs Diminution de l’incidence des IST par 10 Incidence du VIH chez les militaires: : 2.5 / 100 p-a : 0.5 / 100 p-a An example of a population-based intervention is the famous '100% Condom Use Program’ of Thailand. In order to monitor the impact of this programme on behaviour, STI and HIV rates, a series of prospective cohorts of year-old male military conscripts from northern Thailand were surveyed between 1991 and 1993 , with follow-ups at 6-month intervals for incident HIV and STI through to May 1995. Important changes in sexual behaviour were reported, with decreased frequency of sex acts with prostitutes, increased condom use, paralleled by a boom in condom sales. STI incidence showed a huge decline, with a 10-fold decrease from to HIV incidence declined from a rate of 2.5 per 100 person-years during to 0.5 per 100 person-years during

27 Efficacité des Préservatifs
In vitro – 100% (Lytle et al. STD 1990) Pas d’essais randomisės! Cochrane review: 85% efficacitė parmi les couples sėrodiffėrents) (Weller & Davis, Cochrane Database Syst Rev. 2002) Efficacitė varie selon le type de partenaires et la rėgularitė d’utilisation (jusqu’à 95%) (Foss et al. STI 2007)

28 Burkina Faso

29

30 Interventions visant les changements de comportement (1): MSM
Gay Heroes project, USA (Kelly et al, 1997) Initial flagship intervention with peer education - success on reported UAI Gay Men’s Task Force, Scotland (Williamson et al, 2001; Hart & Elford 2003) No impact on behavioural variables, despite increased attendance to GUM clinics; importance of context BIG Project, England (Imrie et al, 2001) despite reported changes in behaviour, higher incidence of STI in intervention group (intensive counselling) 30

31 Unprotected Anal Intercourse (UAI) in serial community samples of gay men (London, ) (N~2000 Each Year) % Source: J. Dodds et al,

32 New Diagnoses of Selected STIs in Men Who Have Sex With Men England & Wales: 1995 to 2001
Diagnoses of many acute STIs in MSM in the UK rose between 1995 and 1999. The greatest proportional rises were in of gonorrhoea, chlamydia and syphilis.

33 Interventions visant les changements de comportement (2): Adolescents
Meta-analysis 26 RCTs (DiCenso et al. BMJ 2002): No increased delays in sexual initiation; no impact on contraception; 1 trial showing impact on undesired pregnancy Mema kwa Vijana (MkV), Tanzania (Ross et al. AIDS 2007) RIPPLE, England (Stephenson et al. 2007) Large school-based RCTs; teacher-led + peer-led curricula Impact on knowledge and on reported changes in behaviour (?linked to knowledge and social desirability) Little or no impact on biological outcomes (HIV, STI, pregnancy) Conclusions: More attention should be given to development of interventions (from theory) Importance of rigorous evaluations to include biological outcomes Importance of including process evaluation to understand failures (and successes?) Review of effective interventions (Steady, Ready, Go! WHO 2007) 33

34 Stratégies de contrôle pour la prévention de la transmission sexuelle du VIH
Réduire l’exposition (c) Réduire la durée de l’infectiosité (D) Traitement des IST et infections intercurrentes augmentant la CV Réduire le risque de transmission (ß) Traitement des IST Circoncision masculine Microbicides vaginaux & méthodes barrières Antirétroviraux (Vaccins) R0 = c  ß  D

35 IST et VIH: Hypothèses de l’effet “cofacteur”
Les IST accroissent la transmission du VIH Le contrôle des IST réduit la transmission du VIH The basis for this strategy revolves around the so called STI-HIV cofactor hypothesis. This hypothesis supposes a real synergy of interaction, whereby STIs would enhance HIV transmission or acquisition (and vice versa) In turn, if proven correct, this cofactor effect would provide means of controlling HIV by controlling STI, and we should be able to demonstrate this.

36 IST et VIH: “Epidemiological synergy”
Le VIH accroît la sévérité et la durée de certaines IST Certaines IST facilitent la transmission du VIH en accroissant l’infectiosité des personnes VIH-positives et/ou la susceptibilité des personnes VIH-négatives IST VIH

37 Effet du VIH sur la presentation clinique de l’herpès génital
Pas de VIH SIDA Courtesy: P. Mayaud

38 Est-ce que les IST accroissent la transmission du VIH
Est-ce que les IST accroissent la transmission du VIH? Fleming DT & Wasserheit JN. Sex Transm Inf 1999; 75: 3-17 1. Preuves épidemiologiques Etudes transversales Etudes prospectives/longitudinales (séroconversion) 2. Preuves biologiques (plausibilité) 3. Etudes d’intervention (essais randomisés) au niveau individual (=efficacité) au niveau communautaire (=efficience) In order to prove this causal association, it is proposed that three strands of evidence come together: First, epidemiological evidence, arising from cross-sectional or prospective epidemiological studies, which can estimate the increase in risk of HIV associated with STIs. The main limitation, at least in the case of cross-sectional studies, is that it is impossible to provide a direction of causality and temporality. Second, biological studies should provide biological plausibility and potential mechanisms explaining the associations that are observed. Finally, intervention studies, best conducted as randomised control trials, would help quantify the effect of STI treatment on HIV incidence. These intervention studies can be conducted at the individual or community level

39 Prospective seroconversion studies: Risk factors for HIV seroconversion in 285 male STI patients in Nairobi, Kenya Cameron DW, et al. Lancet 1989; ii: Here is an example of a prospective study, in which 285 HIV-seronegative men attending an STI clinic in Nairobi were followed up, and their HIV seroconversion status ascertained, and related to a number of risk factors. In this study, the investigators reported that: visiting a sex worker being uncircumcised, and attending the clinic with a genital ulcer were strongly associated with the risk of HIV seroconversion.

40 Plausibilité Biologique: Ulcérations Génitales (UG)
Parmi les VIH -, UG accroissent la susceptibilité: brêches de la muqueuse Recrutement et activation des cellules cibles pour le VIH (ex. CD4+, mDC, CD4) (HD, HSV) co-infection dans les mêmes cellules (ex. HSV) transactivation du VIH (par gènes LTR ou tat) (HSV) rôle des co-récepteurs et chimiokines circulantes (“mucosal synergy” ) (Rebbapragada A, AIDS 2007) Parmi les VIH +, UG accroissent l’infectiosité: virions VIH sont détectés dans les UG (Kreiss JK, JID 1989; Plummer FA, JID 1990) TTT ou guérison des UG entrainent une ↓ du portage génital de VIH (Schacker T, JAMA1998) Ulcères peuvent saigner ! As suggested before, there is apparently a strong epidemiological association between HIV and genital ulcer disease. There are a number of biological arguments to support this as well. (read)

41 When looking at this herpetic ulcer in an HIV-positive patient, it is quite evident that this patient can transmit both viruses!

42 Biological evidence: STIs increase HIV shedding

43 Association between presence of STI and cervico-vaginal HIV-1 shedding in 609 FSWs in Abidjan, Ivory Coast Ghys P, et al. AIDS 1997; 11: F85-93 Further biological plausibility is provided by genital HIV shedding studies. In this study, conducted among 600 female sex workers from Abidjan, the frequency and associated factors of cervicovaginal HIV shedding, were measured. As you can see, HIV-1 shedding was significantly more frequent in women with Neisseria gonorrhoeae, in those with Chlamydia, and those with a cervical or vaginal ulcer, but not in those with Trichomoniasis. Interestingly, the investigators were able to demonstrate a significantly decreased HIV shedding from 42 to 21% in women whose STD were cured. 5

44 Intervention studies: Median concentration of HIV-1 RNA in semen among 135 men with and without urethritis in Malawi Cohen MS, et al. Lancet 1997; 349: treatment x 104 copies/ml Now, onto some intervention studies: first, individual treatment studies. The researchers in this Malawian study, measured HIV-1 RNA concentrations in seminal and blood plasma from 135 men, two thirds of whom had urethritis, and another third recruited from skin clinics to act as controls. This was done before and after treatment of the urethritis. As can be seen, men with urethritis had HIV-1 RNA concentrations in seminal plasma 8 times higher than those in seropositive men without urethritis (despite similar CD4 counts and concentrations of blood plasma viral RNA) After receiving antimicrobial therapy, the concentration of HIV-1 RNA in semen decreased significantly over 2 weeks, to reach comparable levels measured in control patients after 4 weeks. (the blood plasma viral RNA concentrations did not change) 7

45 Est-ce que le contrôle des IST “marche”?
3 essais communautaires randomisés en Afrique de l’Est Mwanza, Tanzanie 1991–95 12 communautés (~ p) (Grosskurth H et al. Lancet 1995; 346: 530-6) Rakai, Ouganda 20 communautés (~ p) (Wawer M et al. Lancet 1999; 353:525-35) Masaka, Ouganda 18 communautés, 3 bras (~ p) (Kamali A et al. Lancet. 2003; 361:645-52) To answer these questions, three large community-based RCT were set up in East Africa, each with a different intervention strategy. First, the Mwanza trial conducted from 1991 to 1995 The trial tried to improve STI care at primary health care clinics in rural Tanzania, using the simplified syndromic management approach. 6 intervention communities and 6 matched control villages were enrolled. The impact of the intervention was assessed in a cohort of 1,000 individuals from each of these villages (12000 people) over a 2 yr-period Second, the Rakai trial in Uganda In this trial, 5 community clusters were randomly assigned to a household-delivered mass STI treatment intervention, and 5 matched villages served as control group. All consenting residents aged years were enrolled; visited in the home every 10 months, sampled and provided with mass treatment (azithromycin, ciprofloxacin, metronidazole in the intervention group, vitamins/anthelmintic drug in the control). About 1000people / village were included. Third the Masaka trial in the neighbouring district to Rakai 18 communities (6 triplets) in rural Uganda were assigned to receive behavioural interventions alone (IEC, group A), behavioural and STI interventions (group B), or routine government health services and community development activities (group C). About 1000 people/village were included in the impact evaluation cohort study.

46 Intervention Characteristics
Mwanza – Syndromic STI management Rakai – Mass STI treatment at 10-monthly intervals Masaka Arm A – Information, education & communication (IEC) Masaka Arm B – IEC plus syndromic STI management

47 Design (community randomised trial=CRT)
Sélection de 6 paires (=12) villages dans la Région de Mwanza, N-O Tanzanie Appariement sur la situation géographique et la prévalence du VIH Randomisation intervention immédiate vs. différée de 2 ans Recrutement 1000 personnes dans chaque village (cluster sampling) Suivi de 2 ans pour incidence VIH, et prévalence et incidence IST DESIGN OF MWANZA IMPACT EVALUATION 12 communities (community=HC + satellite dispensaries) put into matched pairs on basis of locality (urban, roadside etc, STD attendance rates at HC) 6 Intervention & 6 Control Communities Cohort recruited of 1000 individuals/community At baseline samples taken for HIV, urethritis (LED+/Dx/Sx), syphilis, gonorrhoea, Chlamydia Follow-up at 2 years : HIV + tests as above Sexual behaviour survey done on random sample of 1 in 8 cohort members at baseline and F/U. Done to determine whether differences in intervention and control communites is because of change in sex behav.

48 HIV incidence over 2 years in intervention and control communities in the Mwanza trial Grosskurth H et al, Lancet 1995; 346: 38% reduction of HIV 9

49 Conclusions de l’essai de Mwanza
L’amélioration de la PEC des IST a réduit l’incidence du VIH de 38% (Grosskurth H, Lancet 1995) Effet non dû aux changements de comportement Effet probablement dû à la réduction de la durée des infections bactériennes symptomatiques (Mayaud P, AIDS 1997) Intervention hautement coût-efficace: $250 par infection VIH prévenue $11 per DALY (ex. vaccination, IMCI, bednets) (Gilson L, Lancet 1997) Improved STD treatment reduced HIV incidence in this population by 42% over 2 yrs Reduction occurred in both sexes & across matched community pairs This was attributed to reduction of the cofactor effect of STDs by reducing duration of symptomatic bacterial STD as illustrated by a reduction in prevalence of syphilis & symptomatic urethritis Can anticipate reduced incidence of STDs eventually but problem of asymptomatic infections which will not be treated by this approach and which will remain as potential reservoirs of infection in community

50 Summary – Significant Reductions
Rakai Msk A B Mwanza HIV Inc. --- 38% Syphilis Inc. 48% (38%) High Titre Syph Prev. 20% 42% 29% NG Prev. 72% Male urethritis TV Prev. (F) 41% (49%) HSV-2 Inc. 35%

51 Interprétation En Ouganda: Maturité de l’épidemie du VIH
Moins de comportements à risque Prévalence plus faible des IST guérrissables Plus grande proportion d’ulcères HSV-2 La plupart des nouvelles infections VIH acquises de partenaires réguliers (↓ rôle des IST;  rôle de la charge virale VIH) Contrôle des IST: impact variable selon le contexte Que proposer pour le contrôle de l’herpès?

52 Role de l’herpes genital (HSV-2) dans la transmission du VIH
Etudes observationnelles : 25-75% des nouvelles infections par VIH liees a HSV-2 (del Mar Pujades, AIDS 2002) Meta-analyse d’etudes de seroconversion indique risque accru par 2 a 3 chez femmes et hommes (Freeman, AIDS 2006) Elevation des charges virales plasmatiques et dans secretions genitales chez patients co-infectes Plausibilite biologique

53 Impact of HSV reactivations on HIV-1 acquisition
Bacterial vaginosis receptor expression DC-SIGN (dendritic cells) CCR5 (TCD4+, macrophages) CD4 Macrophage Recruitment of cells mDC Infection of susceptible cells iDC (HIV-1 capture) Muco-cutaneous barrier Muco-cutaneous lesions HIV-1 acquisition Van de Perre P, et al. Lancet Infect Dis 2008; 8:490-7

54 Impact of HSV reactivation on HIV-1 replication,
Transactivation of HIV-1 LTR Immune activation Immune deficiency Transmiss.& disease progression HIV-1 replication Bacterial vaginosis receptor expression DC-SIGN (dendritic cells) CCR5 (TCD4+, macrophages) CD4 Macrophage Recruitement of cells mDC Infection of susceptible cells iDC (HIV-1 capture) Impact of HSV reactivation on HIV-1 replication, transmission and disease progression Van de Perre P, et al. Lancet Infect Dis 2008; 8:490-7

55 Contrôle de l’herpès génital pour la prévention de la transmission du VIH
Series d’essais randomises en Afrique, Amerique Latine et USA Approches: Traitement episodique (5j) ou suppressif (3m a 2 ans) Populations: hommes/femmes; VIH+/VIH- Questions de recherche: Traitement épisodique et infectiosité du VIH Traitement suppressif et susceptibilité au VIH Traitement suppressif et infectiosité du VIH Traitement suppressif et transmission du VIH

56 45% 58% 65% 50% 71% 45% 59% 76% 59% 74% 45% 59% 76% 59% 74% 60% 4% 64% 64% Weiss H, et al. ISSTDR London 2009

57 Effet de l’acyclovir sur la guérison des ulcères (et sur le portage génital en HSV-2 et VIH)
Une semaine plus tard Courtesy: P. Mayaud

58 Burkina Faso: VACV among HAART-naive women
Proportion of women with detectable genital HIV-1 RNA Baseline phase Treatment phase Reference: Nagot et al, Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med Feb 22;356(8):790-9. Nagot N, et al. New Engl J Med 2007; 356:

59 Résultats des essais HSV-VIH
Traitement épisodique améliore la guérison des ulceres et le portage lésionnel , mais peu au niveau génital (Mayaud P, JID 2009; Paz-Bailey G, JID 2009; Phiri S, submitted) Traitement suppressif ne prévient pas l’acquisition du VIH (Watson-Jones D, NEJM 2008; Celum C, Lancet 2008) Traitement suppressif réduit l’infectiosité des patients... (Nagot N, NEJM 2007; Zuckerman R, JID 2008 et JID 2009; Baeten J, JID 2008; Dunne E, JAIDS 2008; Delany S, AIDS 2009) Mais ce n’est pas suffisant pour empecher la transmission (Celum C, INEJM in press) Traitement suppressif réduit la CV (-0.33 log en moyenne) et la progression de la maladie (-17%) role comme thérapie adjointe? Recherche nécessaire avant de songer a changer les guidelines !

60 HSV-2-HIV: biological coda
lymphocytes infiltrate genital mucosa Reference Zhu et al. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med Mar 19;204(3): H&E stain of normal epithelium, HSV lesion, and CD8 and HSV-2 in a lesion Zhu et al., J Exp Med 2007; 204: Zhu et al., Nature Reviews 2009

61 Stratégies de contrôle pour la prévention de la transmission sexuelle du VIH
Réduire la durée de l’infectiosité (D) Traitement des IST Promotion de la recherche des soins Dépistage des IST R0 = c  ß  D

62 Stratégies de contrôle pour la prévention de la transmission sexuelle du VIH
Réduire l’exposition (c) Réduire la durée d’exposition (D) Réduire le risque de transmission (ß) Traitement des IST Circoncision masculine Microbicides vaginaux & méthodes barrières Antirétroviraux (Vaccins) R0 = c  ß  D

63 Circoncision masculine: Potentiel pour la prévention du VIH
Données biologiques Cellules de Langerhans dans le prépuce Kératinisation des surfaces (résistance) Données épidemiologiques ↓prévalence VIH chez les hommes circoncis Méta analyse Weiss et al, AIDS 2000;14:2361 38 études (Africaines++): Circoncision ↓risque du VIH de ~50% General population

64 Circoncision masculine: Essais cliniques
Sponsor Population d’essai et endpoint N Resultats ANRS 1265 Incidence du VIH chez les hommes séronegatifs (Orange Farm, South Africa) 3,274 60% réduction Auvert, PLoS Med 2005; 2:1-11 NIAID/NIH & CIHR Incidence du VIH chez les hommes séronegatifs (Kisumu, Kenya) 2,784 53% réduction Bailey, Lancet 2007;369:643-56 NIAID/NIH Incidence du VIH chez les hommes séronegatifs (Rakai, Uganda) 4,996 51% réduction Gray, Lancet 2007;369:657-66 Incidence du VIH chez les femmes (partenaires d’hommes séro+ et séro-) (Rakai, Uganda) 4,000 Abandonné

65 Estimation du nombre de cas d’infection par le VIH dans la region du Kwa Zulu-Natal en 2007 Newell ML, Barninghausen T. Lancet 2007; 369: nouveaux cas d’ infections par VIH prévenus en 2007 (pour pop. ~2.5 million hommes non circoncis)

66 Circoncision masculine : Défis
Passage à l’échelle! (IEC, formation, supervision, coûts) – même efficience? Sécurité et aspects éthiques Acceptabilité culturelle & religieuse Age de la circoncision?

67 Microbicides vaginaux
Echecs: Produits 1ère génération Nonoxynol-9 (COL-1492) (van Damme L, Lancet 2001) Cellulose sulfate/CONRAD/FHI (van Damme L, NEJM 2008) Espoirs: nouvelles formulations (gels, anneaux) et nouveaux produits Acid buffer (Buffer Gel), inhibiteurs d’entrée (Pro2000, Carraguard), surfactants (SAVVY) – (mais abandon des essais Carraguard, SAVVY et un bras de Pro2000…) Pro-2000 : 1er essai avec succes (-30%, ns) en RSA (CROI 2009) A base d’ARV (Tenofovir, Truvada®) +++ Problèmes: éthique, conduite des essais, coût,… Lobbying international… ne pas relâcher les efforts!

68 Barrières cervicales : diaphragmes
Méthode controllée par les femmes Sans danger, efficace et acceptable en contraception Couvre le col, donc ↓ risque infection par VIH & IST Etudes observationnelles: ↓gonorrhée (Rosenberg Z, 2000) Sponsor Population d’essai N Resultats Gates/UCSF Femmes seroneg à Durban, Johannesburg & Harare MIRA vaginal diaphragm with Replens 5,000 (90% Pas superieur au bras ‘placebo’

69 Utilisation des antiretroviraux Potentiel pour la prévention du VIH
“Proof-of-concept” (PMTCT/PTME) PEP (post- exposure [professional] prophylaxis) nPEP (non prof. post-exposure prophylaxis) PrEP (pre-exposure prophylaxis) AHI (acute HIV infection) ART (antiretroviral therapy)

70 PrEP: Espoirs & Challenges
Candidats: Tenofovir & Truvada® Bien tolérés dans le traitement du SIDA Une prise quotidienne Donnees experimentales animales Essais africains (Tenofovir): 900 femmes, pas ↗ effets indésirables, mais inconclusif: 2 vs. 6 seroconversions! Challenges: Implications des infections sous TTT et résistance Niveau de compliance requis? Monitoring des effets secondaires (toxicité hépatique, co-infection) Acceptabilité du TTT au long cours chez des gens en bonne santé? Danger des abus ( & “condom migration”) Danger des mauvais essais!

71 Rôle de ART sur la transmission sexuelle du VIH
Réduction CV plasmatique et génitale (♀♂) => ↓ infectiosité Etude de modellisation prevoit une interruption de la transmission si couverture+++ (WiHO, Lancet 2008) Moins de séroconversions chez des couples sérodifférents: études observationelles aux USA, en Suisse, Italie en Ouganda, au Rwanda, mais pas de d’essais comparatifs...

72 Mais... Toujours 3 a 4 nouvelles infections pour une mise sous traitement Couverture des ARV en Afrique de ~30% Challenges du “scaling up” (human resources, finances, technical) Stigma persiste autour des personnes prenant les ARV (Roura, TMIH 2009) Pour le maximum d’efficacite il faudrait traiter tres tot (au stade AHI – projet CHAVI)

73 % AUC genital tract/plasma
Compartmentalisation of antiretroviral drugs: Diffusion into the female genital tract % AUC genital tract/plasma 0 % 200 % 400 % 600 % ddI (100%) IDV (200%) 3TC (400%) FTC (600%) TDF (400%) ZDV (200%) EFV (0,6%) ABC (150%) d4T (4%) RTV (20%) DLV (20%) Partial treatment of HIV-1 variants replicating within the genital compartment, with selection of HIV-1 resistant variants (Si-Mohamed, JID 2000; Andreoletti, JCM 2007)Driven by poor penetration of ARV in the female genital tract? (Dumond, AIDS 2007) ATV (30%) LPV (30%) Legend : ABC (40%) NRTI PI NNRTI APV (50%) * ND : not determined NVP (80%) SQV (ND) Dumond et al, AIDS 2007

74 Proportion of women with ongoing cervical shedding while on HAART (n=39) in Burkina Faso
Many investigators have shown that there is still ongoing genital replication/shedding of HIV-1 despite good plasma control (eg. Ouedraogo in 60 women up to 56 % had genital hIV-1 detected at least once while on HAART. 30-47% of women on HAART with undetectable plasma HIV-1 RNA had detectable HIV-1 RNA in CVL (Kovacs, Lancet 2001; Cu-Uvin, JAIDS 2006; Nagot, STI 2008) Example from Nagot, STI 2008 on women started on HAART in Burkina faso: Small study of 39 women, 72% detectable CVL RNA, Visit 1 week 18, seen bi-weekly until week 28 just prior to randomisation to 1285b (VCV vs. placebo). Plasma collected only at wk 0, 18, 22 and 28. 34 women had undetectable plasma over this period, 16 (47%) had genital shedding at least once. 5 women had detectable PVL at w28, 6 had detectable CVL RNA W28. Only including visits with detectable genital HIV-1 RNA, Mean genital HIV-1 RNA was 3.87 log before HAART, reduced by 0.83 log while on HAART. We are investigating whether there is a link between genital replication and subsequent plasma viral escape, and/or resistance development Nagot N, et al. STI 2008; 84:

75 Interventions pour la prévention de la transmission (sexuelle) du VIH
Réduire les comportements à risque Traiter les IST VCT Infecté Infection récente Non infecté Barrières Circoncision Microbicides Vaccins PREP/PEP Traitement IO PTME Traitement ARV Adapted from Cates W, Jr

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