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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.

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Jérôme LeGoff HEGP – Inserm U743

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  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

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