1 / 21

Jérôme LeGoff HEGP – Inserm U743

Impact of HSV-2 episodic therapy on HIV-1 and HSV-2 genital shedding, and ulcer healing among women in Ghana and Central African Republic. ANRS 1212 Study. Jérôme LeGoff HEGP – Inserm U743. Background.

xanti
Télécharger la présentation

Jérôme LeGoff HEGP – Inserm U743

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Impact of HSV-2 episodic therapy on HIV-1 and HSV-2 genital shedding, and ulcer healing among women in Ghana and Central African Republic ANRS 1212 Study Jérôme LeGoff HEGP – Inserm U743

  2. Background • HSV-2 infection increases the risk of HIV acquisition by 3-fold (Wald & Link, 2002; Freeman et al, 2006) • HIV transmission is enhanced in the presence of genital ulcer disease (GUD) (Gray, Lancet 2001) • Increasing % of GUD due to HSV-2 in HIV+ Research questions • Is HSV-2 really a cofactor of HIV transmission? • Can HSV-2 infection control have an impact on HIV transmission? • By which method? • Prevention of GUD (role of suppressive therapy) • Treatment of GUD (role of episodic therapy) • Other (education, condoms, microbicides, vaccine?)

  3. Study Design Multicentre, randomised, double-blind placebo-controlled trial Syndromic Mx + Placebo Ciprofloxacin + Benzathine penicillin 2.4 MU D2  D4  D7  D14  D28 Randomisation Syndromic Mx + Acyclovir ACV 400 mg x 3/d - 5 days D0 Outcomes* HIV-1 RNA Lesional, genital and plasma HSV-2 DNA Lesional and genital Ulcer aetiologies Ulcer healing Acrra/Kumasi Bangui *LeGoff J et al, J Clin Microbiol 2006;44: 423-32

  4. ResultsatBaseline

  5. 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% HSV-2prevalence HIV-1 prevalence 96% 100 P<0.01 P<0.001 80 64% 57% 60 40 20 10% 0 HIV+ HIV- HSV2+ HSV2-

  6. 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%

  7. 6 5 4 3 2 1 0 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 Freq HSV-2 shedding Mean CVL HSV-2 DNA % 100 NS P<0.001 80 60 log10 copies/ml 40 3.85 4.13 54% 20 23% HIV+ HIV- HIV+ HIV- 0 N=184 N=204 N=98 N=47 Genital HSV-2 shedding occured more frequently among HIV-1 + women

  8. 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) 100 6 P=0.001 P=0.003 5 80 4 60 3 40 2 68% 42% 3.14 2.1 20 1 HSV-2 DNA 0 0 Positive Negative Positive Negative N=109 N=71 Genital HIV-1 shedding among women shedding HSV-2: • Occured more frequently • Associated with higher viral loads • 1 log10 CV HSV-2 DNA  2-fold CV HIV-1 RNA

  9. Correlations between cervico-vaginal HSV-2 DNA and plasma HIV-1 RNA  1 log10 CV HSV-2 DNA  1.7 fold plasma HIV-1 RNA log10 copies/mL Spearman = 0.24 P=0.001 6 P=0.07 5 6 4 5.5 5.10 4.65 5 3 4.5 Median Plasma HIV-1 RNA (log10 copies/mL) 4 2 3.5 1 3 2.5 0 Positive Negative 2 0 1 2 3 4 HSV-2 DNA CV HSV-2 DNA (log10 copies/mL)

  10. ResultsImpact Study

  11. Enrolment, follow-up, compliance Primary analysis group: 118 HIV+ women with HSV-2 ulcer 64 HIV+ with HSV2 ulcer 54 HIV+ with HSV2 ulcer 52 analysed on day 7 (81%) 42 analysed on day 7 (78%) 490 women presented Mean compliance rate (pill count) = 99% in both arms Side effects = 8/441 (2%, severity 1 or 2) 449 eligible 441 randomized 220 Placebo arm 221 ACV arm

  12. SM+Placebo (n=64) SM+ACV (n=54) Mean age in years 31.4 30.8 Median CD4 count (/µL) (IQR) 188 (72-519) 194 (92-548) Mean plasma HIV-1 RNA (CI) 4.63 (4.1-4.9) 4.76 (4.3-5.1) Taking HAART 8% 11% Experienced GUD last year 42% 47% NG/CT/TV 5% 6% Serological syphilis TPHA/RPR+ 3% 3% Participants characteristics in primary analysis group (HIV+ women with HSV-2 ulcers) (N=118)

  13. Impact of ACV on HIV-1 RNA at day 7 Cervico-vaginal detection RR*=0.97 (0.8 - 1.2) % * Adjusted for baseline CV HIV-1 RNA 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)

  14. Impact of ACV on frequency of lesional HIV-1 RNA detection at day 7 RR=0.75 (0.3 – 2.0) %

  15. 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 log10copies/mL lower in acyclovir arm than placebo arm (P=0.005)

  16. Proportion of women with cervico-vaginal HIV-1 RNA and HSV-2 DNA over time HIV-1 RNA HSV-2 DNA

  17. D0 D7 Magnitude P- value Plac. ACV Plac. ACV % ulcers with >90% size reduction* 44% 55% RR=1.26 0.25 % with ulcers <10 mm2 10% 0% 42% 58% RR=1.60 0.03 Impact on ulcer healing at day 7 in HIV+ women with HSV-2 ulcers * Excluding ulcers size <10 mm2 at baseline

  18. Ulcer healing rates over time:HIV+ women with HSV-2 ulcers Some impact of ACV among HIV+ women with HSV-2 ulcers (P=0.10) Ulcers healed faster in women with higher CD4 count (P=0.0002)

  19. ANRS1212: Conclusions Genital Ulcer Asymptomatic Shedding > x 10 x 2.5 • 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 (Baeten JID 2004)

  20. ANRS1212: Conclusions • 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

  21. 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) Acknowledgements • 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

More Related