HIV/STDs and Excretion of HIV in Genital Secretions - Implications for sexual transmission. Pietro L. Vernazza, KSSG, St. Gallen, Switzerland

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1 HIV/STDs and Excretion of HIV in Genital Secretions - Implications for sexual transmission Pietro L. Vernazza, KSSG, St. Gallen, Switzerland

2 Where it all began...

3 Vogt M, Lancet, 8. March 86

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6 Schultz et al. BMJ 1999;319:

7 VL and HIV-Transmission-Risk 30 Rakai (Uganda) 453 HIV-disc. couples 11.6 % TR / year % partners infected < '000 10'000-50'000 HIV-RNA load (cp/ml) >50000 Quinn, NEJM, 2000; 342:921-9.

8 HIV-RNA in blood and semen Blood HIV-RNA (log 10 cp/ml) r = 0.80 P < Group BL - PHI Early PHI Late PHI Seminal plasma HIV-RNA (log 10 cp/ml) Vernazza, 2000, Quest-Study Group

9 Genital and blood VL in women r=0.52 p= Kovacs et al, Lancet 2001; 358:

10 HIV-RNA (log 10 cp/ml) Viral load in blood vs. semen during the course of treatment in PHI HIV-DNA (log 10 c/ejac) RNA blood RNA seminal fluid DNA seminal cells 1 N=32 N=22 N=22 N=39 Baseline Early Late Acute & Primary HIV Infection CAD

11 Summary 1 HIV in genital tract follows blood VL Q: Is there a genital compartment Q: What is the effect of treatment

12 HIV in semen under HIV therapy >1 log drop <0.5 log drop Vernazza P. et al, AIDS, 1997;11:

13 Vaginal HIV under HIV therapy Blood Vagina Hart C. et al, JID, 1999;179:871-82

14 HIV in Semen during HAART patients (%) with pos. HIV detection in semen 100% 80% 60% 40% 20% p< No Therapy (control) HAART, RNA<400 p=0.025 n=55 n=114 0% HIV-RNA HIV-DNA Vernazza et al, AIDS, 2000, 14;117-21

15 HAART: Latent HIV in seminal cells 28 men Supressive HAART PBMC and SC Viral growth 2-LTR-circular DNA % positive Viral Cx PBMC 2-LTR-circ DNA Seminal Cells Nunnari G. et al, AIDS, 2002; 16:39-45

16 QUEST: HIV-RNA in semen during tx HIV-RNA (log 10 cp/ml) Plasma RNA Semen RNA # Days on Therapy

17 QUEST: HIV-DNA in semen during tx HIV-DNA (log 10 /Ejac.) Plasma RNA Viral DNA / ejaculate # Days on Therapy

18 CAse HSV Seattle Courtesy slide: L. Corey

19 Malawi urethritis project: HIV-RNA in semen log 10 HIV-1 RNA copies/ml BL Wk2 BL Wk1 Wk2 BL Wk1 Wk2 BL Wk1 Wk2 Dermatology Urethritis GC NGU Cohen et al, Lancet 1997; 349:

20 Local inflammation and genital shedding of HIV: Men Coombs et al, AIDS, 2003;17:455-80

21 Tx of Cervicitis and Shedding of HIV Before Tx After Tx 5 HIV-RNA / swab p=0.02 p=0.02 p=0.66 p< n= N. gonorh. 16 Chl. trach. 7 unspecific 13 combined 36 McClelland et al, AIDS 2001; 15:

22 Tx of Cervicitis and Shedding of HIV Before Tx After Tx detectable HIV-DNA (%) n= N. gon. 16 C. trach. 7 unspec. 13 combined 36 McClelland et al, AIDS 2001; 15:

23 Local inflammation and genital shedding of HIV: Women Add table 2 from coombs Coombs et al, AIDS, 2003;17:455-80

24 Effect of HSV on genital HIV 200 women, HSV-2 and HIV seropos. 71 with detectable cervical HSV-2 cervical HSV-level (per log 10 ) assoc. w. HIV-RNA 1.35-fold ( ) HIV-DNA 1.36-fold ( ) McClelland et al, AIDS 2002;

25 Urethritis during HAART (n=24) Plasma HIV-RNA Semen HIV-RNA 2 / 20 positive (low level) 4 / 4 positive (high level) Sadiq et al, AIDS 2002;16:219-25

26 Summary 2 HIV in genital tract follows blood VL Compartmentalized HIV-shedding possible with local inflammation Q: Contribution of cells vs. free HIV in STDs?

27 PHI Transmission couple 22 y/o woman AUG y/o man HIV-RNA log 10 /ml or Ejac Blood plasma Seminal plasma Seminal cells (DNA) HIV-Ag C.trach.-PCR -+ + AZT+3TC+ABC+APV AZM

28 HIV-DNA and RNA in semen during PHI (QUEST-Study) 5 Seminal cell HIV-DNA (log 10 cp/ejac) Group BL - PHI Seminal plasma HIV-RNA (log 10 cp/ml)

29 Viral load in female genital tract Blood DNA r =.64 Blood RNA Andreoletti, JID, 2003;189:549-54

30 Viral load in female genital tract Genital RNA r =.50 Blood RNA Andreoletti, JID, 2003;189:549-54

31 Viral load in female genital tract Genital DNA r =.31 Blood DNA Andreoletti, JID, 2003;189:549-54

32 Viral load in female genital tract Genital DNA r =.11 Genital RNA Andreoletti, JID, 2003;189:549-54

33 Zhu et al. Transmitted HIV in semen Zhu et al, 1996, JVirol

34 Cell-free vs. Cell-associated trm Long et al, Nat Med, 2000; 6:71-5

35 HIV diversity develops over time infection 6 mt time

36 HIV diversity in early infection Men: 1 pattern <5% diversity: homogenous pattern Women: 2 patterns homogenous pattern heterogenous pattern

37 Potential hypotheses Infected by different partners Similar # sex acts / wk Similar fraction with single partner Phylogenetic clustering Differences in immune response 5/6 w already heterogenous before s/c Difference in transmitted virus

38 Hypothesis Sex. Trsm of HIV = rare event 1 hit One single hit could be Free virus HIV-infected cell Multiple strains Cell-associated

39 HIV-diversity, STDs and DNA 156 female sex workers, Kenya 89 heterogenous, 67 homogenous viral strain Sagar, AIDS, 2004;18:615-9

40 Summary 3 HIV in genital tract follows blood VL Compartementalised HIV-shedding possible with local inflammation Cell-associated HIV-DNA needs more attention STD-associated transmission might be more cell-associated