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Opportunities and Challenges in reducing heterosexual HIV transmission: Condoms, anti-retroviral chemoprophylaxis, HSV-

Opportunities and Challenges in reducing heterosexual HIV transmission: Condoms, anti-retroviral chemoprophylaxis, HSV-2 control and male circumcision. Quarraisha Abdool Karim Columbia University Fogarty AIDS Training & Research Program CAPRISA, University of KwaZulu-Natal, South Africa.

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Opportunities and Challenges in reducing heterosexual HIV transmission: Condoms, anti-retroviral chemoprophylaxis, HSV-

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  1. Opportunities and Challenges in reducing heterosexual HIV transmission: Condoms, anti-retroviral chemoprophylaxis, HSV-2 control and male circumcision Quarraisha Abdool Karim Columbia University Fogarty AIDS Training & Research Program CAPRISA, University of KwaZulu-Natal, South Africa

  2. Overview • Global burden of heterosexual transmission • Epidemiology • Biological mechanisms • HIV Prevention • Proven methods:- Condoms (male and female) • Potential new strategies: • ARV chemoprophylaxis • HSV-2 control thro prevention and/or treatment • Male circumcision • Evidence that HIV Prevention works! • Conclusion

  3. Global burden: Role of heterosexual transmission in 2003 *(conservative estimate) Source: Joint UNAIDS and WHO AIDS epidemic update 2004

  4. Global burden: Modes of transmission in 2003 Eastern Europe & Central \Asia 1.3 milion IDU Western Europe 580 000 MSM, IDU North America 1.0 million HSex,MSM, IDU East Asia 900 000 HSex,IDU, MSM North Africa & Middle East 480 000 HSex, IDU Caribbean 430 000 HSex, MSM South & South-East Asia 6.5 million HSex, IDU Sub Saharan Africa 25.0 million HSex Latin America 1.6 million HSex,MSM, IDU Oceania 32 000 MSM HSex = heterosexual transmission IDU = transmission through injecting drug use MSM = sexual transmission among men who have sex with men Source: Joint UNAIDS and WHO AIDS epidemic update 2004

  5. Epidemiology:Gender differences Age and gender specific prevalence of HIV infection in rural South Africa 10 Male Female 8 JUN/JUL 92 6 Prevalence (%) 4 2 0 <9 10-14 15-19 20-24 25-29 30-39 40-49 Source : Abdool Karim Q et al, AIDS 1992

  6. Epidemiology:Age trends Temporal trends in the age-specific HIV prevalence (%) in ANC attendees in rural South Africa Sources: Wilkinson et al, JAIDS Abdool Karim S et al, CAPRISA application, NIH - 2002

  7. Epidemiology: Mobility and Migration HIV Prevalence Rural Populations Mobile Stable RR Tanzania 11.6% 3.6% 3.2 Source: Bloom et al, Sex Transm Infect 2002 Uganda 14.5% 4.9% 3.0 Source: Nunn et al, AIDS 1995 South Africa 25.9% 12.7% 2.0 Source: Lurie et al, Sex Transm Dis 2002

  8. Epidemiology: Sexually Transmitted Diseases Laga 93 OR Dominiguez 96 OR Orroth 00 OR Celentano 96 IRR Mbizvo 96 IRR Figueroa 97 RR Nopkesorn 98 OR Orroth 00 OR combined 5 10 1 Effect Source: Rottingen J-A et al, Sex Transm Dis 2001

  9. Mechanisms: Semen and the Vagina • Semen and vaginal secretions have: • T cells and macrophages which contain HIV, and • cell free virus • Hence their ability to transmit HIV • Vasectomy does not reduce HIV shedding in semen Unresolved issues • Sources of infectious HIV: cell-associated vs cell-free • Targets of infectious HIV: • Are epithelial cells an important target of HIV? • Are immune cells in mucosa or lumen primary targets? • Are breaks in vaginal/penile epithelium necessary? Source: Vernazza PL et al, AIDS 1999

  10. Mechanisms: Immune status and risk of transmission Presence of HIV in semen and vaginal secretions HIV-RNA PCR Cervico-Vaginal Lavage Semen % positive % positive  CD4 count (x106/L) 71 0-199 73 69 200-500 61  40 >500 17 Source: Vernazza PL et al, AIDS 1997 Natividad-Villanueva GU et al, Int J STD & AIDS 2003

  11. Mechanisms: Estimates of per-contact HIV risk *conservative estimates

  12. Goal: Prevent sexual HIV transmission Reduce discordant sexual acts Failing which Reduce the probability of transmission in discordant sexual acts Proven prevention: condoms (male and female) Unproven: ARV chemoprophylaxis HSV-2 prevention / treatment, Male circumcision

  13. Prevention: • Condoms - effective barrier • Treponema pallidium (syphilis) • Neisseria gonorrhoeae (gonorrhea) • Human immunodeficiency virus (HIV) • Human sperm Source: Family Health International / Hill Studio. This illustration appeared in the monograph: The Male Latex Condom: Recent Advances, Future Directions

  14. Prevention: Male Condom effectiveness • Consistent condom use reduces HIV incidence by at least 80% (but may be as high as 97%) Source: Weller S & Davis K, The Cochrane Library 2004 • Sero-conversions in discordant couples who used • condoms: • Consistently = 0% per person-year (n=124) • Inconsistently = 4.8% per person-year (n=121) • Source: De Vincenzi I, N Engl J Med 1994 • For protection against unintended pregnancy, condoms are 86% - 97% effective Source: Trussel et al, Contraceptive Technology 1998.

  15. Prevention: Successful male condom promotion in South Africa 400 Distribution in millions of pieces 358 Million Investment in millions of Rand 300 Projected distribution pieces 267 Million 250 Million Condom Pieces / Millions of Rands 200 Projected cost 100 R103,8m @R0,29c R61,4m @R0,23c R47,5m @R0.19c FY2000 FY2001 FY2002 Fiscal Year Distribution / Cost Source: Wilson J, N DOH Logistics 2003

  16. Prevention: Fate of condoms in South Africa • Followed 384 sequential condom recipients and their 5528 condoms for 5 weeks • Condoms after 5 weeks: • 43.7% had been used • 21.8% given away • 8.5% lost or discarded • 26.0% still available for use • Wastage at 5 weeks - less than 10% Source: Myer L et al,AIDS 2001

  17. Prevention: Female Condom Effectiveness • In-vitro data support impermeability to HIV Source: Drew W et al, Sex Trans Dis 1990 • As effective as male condoms in preventing STIs Source: French PP et al, Sex Trans Dis 2003; Fontanet et al, AIDS 1998; Feldblum et al, AIDS 2001 • Female condom prevented semen exposure in 79-93% of users Source: Farr G et al, Am J Epidemiol 2003 However, does the promotion of the female condom have a negative impact, a positive impact or no impact on male condom use?

  18. Prevention: Female condoms in prevention programs increase overall condom use 80 72,0 69,6% 67,7 65,8 70 Male condom use at the beginning of the study 60 50 Male and female condom use at the end of the study % 35,7 40 33,5% 31,6 29,7 30 20 10 0 Total Community Health care setting Combined Proportion of safe sex acts in the last sexual intercourse at start and end of female condom promotion in various health care settings in Brazil Source: Barbosa R et al, XIIIth Int AIDS Conference, 2000

  19. Potential, but yet unproven, strategies to prevent sexual transmission of HIV: What is the evidence, in the absence of randomised control trials, to suggest this strategy may prevent heterosexual HIV transmission? • ARV chemoprophylaxis

  20. <400 <400 <400 >50 000 >50 000 >50 000 400-3499 400-3499 400-3499 3500-9999 3500-9999 3500-9999 10 000-49 999 10 000-49 999 10 000-49 999 ARV Prophylaxis: Rationale for ART to reduce heterosexual HIV transmission 30 Female-to-Male Transmission Male-to-Female Transmission All subjects 25 20 15 Transmission rate per 100 Person-Years 10 5 0 Viral load (HIV-1 RNA copies/ml) and HIV transmission Source: Quinn N, et al,N Eng J Med 2000

  21. ARV Prophylaxis: Preliminary data and remaining challenges • Mathematical models estimateup to 80% HIV reduction Sources: Blower S et al, Science 2000; Gray R et al, Lancet 2001; Law M et al, AIDS 2001 • An observational study: 50% reduction in HIV transmission in discordant couples on AZT alone Source: Musicco M et al, Arch Intern Med, 1994 • Need “Proof of concept” + “Feasibility of intervention” HPTN 052 (PI: Cohen) – currently underway • Challenges: • HIV status - Need well developed VCT • Functioning health care infrastructure to provide care & drugs • Increased risk behaviours may offset benefits • If adherence is suboptimal, drug resistance may increase • Cost

  22. Potential, but yet unproven, strategies to prevent sexual transmission of HIV: What is the evidence, in the absence of randomised control trials, to suggest this strategy may prevent heterosexual HIV transmission? • HSV-2 prevention & • HSV-2 treatment

  23. HSV-2 control: Rationale for HSV-2 control to reduce HIV transmission • HSV-2 may increase risk of transmitting HIV: • Sub-clinical HSV-2 reactivation elevates blood HIV RNA Source: Corey L et al, J Acquir Immune Defic Syndr, 2004 • HSV-2 may increase risk of acquiring HIV: • Recent symptomatic GUD (genital ulcer disease) in HIV+ person increases probability of transmission per act - 4 fold Source: Grosskurth et al, Lancet 2000 • HSV-2 most common cause of GUD • Antivirals can reduce HSV-2 transmission: • Daily valcyclovir can reduce HSV-2 transmission among HSV-2 discordant heterosexual couple Source: Corey L et al, N Engl J Med 2004 • HSV-2 vaccines – may be future of HSV-2 prevention • Hence: HSV-2 control may reduce HIV transmission

  24. HSV control: Rationale for HSV-2 control to reduce HIV transmission Source: Wawer M et al, Lancet 1999

  25. HSV-2 control: Preliminary data and remaining challenges • HIV-1 incidence about 13-fold higher in rural Tanzanian men with incident HSV-2 compared to about 6-fold higher in those men with prevalent HSV-2 infection Source: del Mar Pujades Rodriquez M et al, AIDS, 2002 • HIV-1 incidence almost 4-fold higher with incident HSV-2 infection in Pune sex workers and their clients Source: Reynolds et al, Lancet 2004 • Need “Proof of concept” trial HPTN 039 (PI: Celum) – currently underway • Challenges: • Need to know HSV-2 status – though may work in HSV-2 + or HSV-2 - • Daily drug therapy for prophylaxis – infrastructure to distribute drugs • Increased risk behaviours may offset benefits • Drug resistance • Cost

  26. Potential, but yet unproven, strategies to prevent sexual transmission of HIV: What is the evidence, in the absence of randomised control trials, to suggest this strategy may prevent heterosexual HIV transmission? • Male Circumcision

  27. Cameron 89 CS Lavery 99 CS Mehendale 96 CS Talzak 93 CS Bwayo 94 C-SS Diallo 92 C-SS Gilks 92 C-SS Greenblatt 88 C-SS Lankoande 98 C-SS Mehendale 96a C-SS Nasio 96 C-SS Pepin 92 C-SS Simonsen 88 C-SS Tyndal 96 C-SS Vaz 95 C-SS Carael 88 C-SS MacDonald 01 CC Sassan 96 CC 5 0.1 10 0.2 1 Favours circumcision Favours no circumcision Male circumcision: Observational studies suggest protective benefit in high-risk groups • Important biases • & confounders: • Sexual behaviour • Religion • Penile hygiene • Viral load / CD4+ cells Source: Siegfried N et al, Cochrane Library 2004

  28. Male circumcision: Rationale for circumcision to reduce HIV transmission • Foreskin has Langerhans cells with CD4 and other receptors that facilitate viral entry Sources: Szabo R, Br Med J 2000; Soto-Ramirez E, Science 1996 • Immunofluorescence of foreskin mucosa – more susceptible to HIV infection than cervical mucosa Source: Patterson B et al, Am J Pathol 2002 • Evidence from discordant couples: HIV incidence in HIV- Ugandan men in discordant couples was 0%(n=50) versus 16.7%(n=137) in circumcised & uncircumcised Source: Gray R et al, AIDS 2000 • Not all effects of circumcision are beneficial: Inner foreskin has apocrine glands which secrete lysozyme that kills HIV and may be protective Source: Fleiss 98, Cold 99

  29. Male Circumcision: Lack of association with HIV in the General Population Gray 00 CS Auvert 01 C-SS Auvert 01a C-SS Auvert 01b C-SS Auvert 01c C-SS Auvert 01d C-SS Barongo 92 C-SS Barongo 94 C-SS Barongo 95 C-SS Grosskurth 95 C-SS Kelly 99 C-SS Kisesa 96 C-SS Seed 95 C-SS Serwada 92 C-SS V/d Perre 87 C-SS Pison 93 CC 0.1 0.2 5 10 1 Favours no circumcision Favours circumcision Source: Siegfried N et al, Cochrane Library 2004

  30. Male circumcision:Current and remaining challenges • Current evidence is insufficient to consider male circumcision as a public health intervention • 3 Randomised control trials currently underway: • Kenya (PI: Baily) • Uganda (PI: Gray) • South Africa (PI: Auvert) • Challenges: • Feasibility & acceptability of widespread male circumcision, • Surgical intervention with a noteworthy complication rate • Sexual practices post-circumcision do not offset benefit • Need skilled HCWs to perform circumcisions • Costs….

  31. From research findings to real world implementation: Can implementation of interventions for heterosexual transmission, which show efficacy in research settings, lead to reduction of HIV transmission and control at country level?

  32. Prevention of heterosexual HIV works! Evidence from Uganda 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 Source: Stoneburner R et al, Science 2004

  33. Prevention of heterosexual HIV works!Evidence from the Thai100% condom promotion program 4.5 4.0 3.5 Male conscripts (age 21) 3.0 2.5 Prevalence (%) 2.0 Pregnant women 1.5 1.0 Donated blood 1.0 0.0 Dec 92 Dec 93 Dec 94 Dec 95 Dec 89 Dec 90 Dec 91 Jun 89 Jun 90 Jun 91 Jun 92 Jun 93 Jun 94 Jun 95 Jun 96 Jun 97 Jun 98 Jun 99 Jun 00 Jun 01 Jun 02 Source: Thailand Ministry of Public Health

  34. CONCLUSION • Promotion of male condoms to reduce HIV- it does work! • Current proven strategies for prevention of heterosexual HIV transmission can control HIV in developing countries • Promotion of female condoms in addition to male condoms can increase overall condom use • Preliminary data suggest that ARV prophylaxis, HSV-2 control and male circumcision may be able to reduce HIV transmission - clinical trials to show this are underway: We patiently watch this space for these critically important clinical trial data in …….Toronto 2006!

  35. Acknowledgements • CAPRISA: Salim Abdool Karim, Cheryl Baxter, Hirut Gebrekristos and Francois Loggerenberg • The NIH’s CIPRA program & Fogarty Centre • Columbia University: Zena Stein, Angela Merges • HPTN: Ward Cates, Myron Cohen • International Partnership for Microbicides

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