Opportunities and Challenges in reducing heterosexual HIV transmission:

Opportunities and Challenges in reducing heterosexual HIV transmission:

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 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 Global burden: Role of heterosexual transmission in 2003 Number HIV infected* Estimated % due to heterosexual

transmission Persons living with HIV 37.8 million 87% New infections 4.8 million 86% Estimated deaths 2.9 million 88% *(conservative estimate) Source: Joint UNAIDS and WHO AIDS epidemic update 2004 Global burden: Modes of transmission in 2003 Eastern Europe & Western Europe Central \Asia 1.3 milion 580 000

North America 1.0 million MSM, IDU HSex, MSM, IDU Caribbean 430 000 North Africa & Middle East 480 000 HSex, MSM Latin America 1.6 million HSex, MSM, IDU HSex IDU MSM HSex, IDU IDU East Asia 900 000

HSex, IDU, MSM South & South-East Asia 6.5 million HSex, IDU Sub Saharan Africa 25.0 million HSex Oceania 32 000 MSM = heterosexual transmission = transmission through injecting drug use = sexual transmission among men who have sex with men Source: Joint UNAIDS and WHO AIDS epidemic update 2004 Epidemiology: Gender differences 10 Male Female Prevalence (%)

8 JUN/JUL 92 6 4 2 0 <9 10-14 15-19 20-24 25-29 30-39 40-49 Age and gender specific prevalence of HIV infection in rural South Africa Source : Abdool Karim Q et al, AIDS 1992 Epidemiology: Age trends Age Group 1992 1995

1998 2001 20-24 6.9 21.1 39.3 50.8 25-29 2.7 18.8 36.4 47.2 30-34 1.4 15.0

23.4 38.4 35-39 0.0 3.4 23.0 36.4 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 Epidemiology: Mobility and Migration Rural Populations Tanzania HIV Prevalence Mobile Stable RR

11.6% 3.6% 3.2 14.5% 4.9% 3.0 25.9% 12.7% 2.0 Source: Bloom et al, Sex Transm Infect 2002 Uganda Source: Nunn et al, AIDS 1995 South Africa Source: Lurie et al, Sex Transm Dis 2002 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 1 Source: Rottingen J-A et al, Sex Transm Dis 2001 5 Effect 10 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 Mechanisms: Immune status and risk of transmission Presence of HIV in semen and vaginal secretions

CD4 count (x106/ L) HIV-RNA PCR Cervico-Vaginal Semen Lavage % positive % positive 0-199 71 73 200-500 61 69 >500 40 17 Source: Vernazza PL et al, AIDS 1997 Natividad-Villanueva GU et al, Int J STD & AIDS 2003

Mechanisms: Estimates of per-contact HIV risk Exposure Needle sharing Source: Kaplan & Heimer 1992 Occupational needle stick Risk per 10,000 contacts* 60 Source: Gerberding 1995 33 Receptive anal 80 Source: DeGruttola 1989 Receptive vaginal Source: Peterman 1996; Padian 1991 Insertive anal and vaginal Source: Padian 1991; Downs 1996 Receptive vs Insertive vaginal sex *conservative estimates

20 3 +7:1 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 Prevention: Condoms - effective barrier A. B. C. D. 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 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. Condom Pieces / Millions of Rands Prevention: Successful male condom promotion in South Africa 400 Distribution in millions of pieces

358 Million 300 200 Investment in millions of Rand Projected distribution pieces 267 Million 250 Million Projected cost 100 R61,4m @R0,23c R47,5m @R0.19c FY2000 FY2001

Fiscal Year Distribution / Cost Source: Wilson J, N DOH Logistics 2003 R103,8m @R0,29c FY2002 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 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? Prevention: Female condoms in prevention programs increase overall condom use 80 70 72,0 69,6% 67,7 65,8 Male condom use at the beginning of the study 60

% 50 40 33,5% 30 35,7 29,7 31,6 Male and female condom use at the end of the study 20 10 0 Total Community Health care settingCombined 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

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 30 Female-to-Male Transmission Male-to-Female Transmission All subjects 25 20 15 10 >50 000 10 000-49 999 3500-9999

400-3499 <400 >50 000 10 000-49 999 3500-9999 400-3499 <400 >50 000 10 000-49 999 3500-9999 0 400-3499 5 <400 Transmission rate per 100 Person-Years

ARV Prophylaxis: Rationale for ART to reduce heterosexual HIV transmission Viral load (HIV-1 RNA copies/ml) and HIV transmission Source: Quinn N, et al, N Eng J Med 2000 ARV Prophylaxis: Preliminary data and remaining challenges Mathematical models estimate up 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

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 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 HSV control: Rationale for HSV-2 control to reduce HIV transmission Probability of HIV infection in the HIV- partner per 10 000 contacts HIV plasma RNA in the HIV+ partner (copies/ml) HSV+ HSV- <1700 10 0.4 1700-12,499 23 5 12,500-38,499 18

2 >38,500 36 7 Source: Wawer M et al, Lancet 1999 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 HSV2 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 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 Male circumcision: Observational studies suggest protective benefit in high-risk groups Cameron 89 CS Lavery 99 CS Mehendale 96 CS Talzak 93

CS Bwayo 94 C-SS Important biases & confounders: Sexual behaviour Religion Penile hygiene Viral load / CD4+ cells 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 Sassan 01 96 CC CC 0.1 0.2 Favours circumcision Source: Siegfried N et al, Cochrane Library 2004 1 5 10 Favours no circumcision 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 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 Favours circumcision Source: Siegfried N et al, Cochrane Library 2004

1 5 10 Favours no circumcision 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.

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

1999 Prevention of heterosexual HIV works! Evidence from the Thai 100% condom promotion program 4.5 4.0 Prevalence (%) 3.5 Male conscripts (age 21) 3.0 2.5 2.0 Pregnant women 1.5 1.0 Donated blood 1.0 Source: Thailand Ministry of Public Health

Jun 02 Jun 01 Jun 00 Jun 99 Jun 98 Jun 97 Jun 96 Dec 95 Jun 95 Dec 94 Jun 94 Dec 93 Jun 93 Dec 92 Jun 92

Dec 91 Jun 91 Dec 90 Jun 90 Dec 89 Jun 89 0.0 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! Acknowledgements CAPRISA: Salim Abdool Karim, Cheryl Baxter,

Hirut Gebrekristos and Francois Loggerenberg The NIHs CIPRA program & Fogarty Centre Columbia University: Zena Stein, Angela Merges HPTN: Ward Cates, Myron Cohen International Partnership for Microbicides

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