1. Critical linkages in prevention: HIV and STIs Jessica Justman, M.D. Center for Infectious Disease Epidemiologic Research Mailman School of Public Health, Columbia University Division of Infectious Diseases College of Physicians and Surgeons, Columbia University & Bronx-Lebanon Hospital Center April 30, 2009 HIV Center Rounds

2. Critical linkages in prevention: HIV and STIs Compare STI and HIV prevention –Terms: HIV vs STI –Biomedical perspective Do STIs get lost in the discussion on HIV prevention? –If so, why? –What should be done?

3. HIV and STIs: Overview Brief comparison of pathophysiology and epidemiology of STIs and HIV Approaches to prevention: efficacy data – Condoms—male and female – Male circumcision – STI treatment – Topical microbicides – PrEP, ART How to re-focus on STI prevention

4. HIV and STIs: comparison of pathophysiology HIV Intraepithelial CD4 and LC as primary targets Mucosal breaks Innate immune system builds clusters of infected cells OIs and death N. gonorrhea Columnar epithelial cells as primary target Submucosal infection 24-48 hrs later Purulent cervicitis, rarely systemic Resolution in most

5. Nature Reviews Microbiology 1, 25-34 (2003) Cervical mucosa disruptable single layer

6. HIV and STIs: Comparison of epidemiologic features Similar Populations –Sub Saharan Africa Risk factors –Freq unprot intercourse –Different partners Geographic locations –Hotspots based on sexual networks

7. Similar Geographic Hotspots: NYC PLWA as % of Population Chlamydia in Women Gonorrhea in Women

8. HIV and STIs: Comparison of epidemiologic features Similar Populations –Sub Saharan Africa Risk factors –Freq unprot intercourse –Different partners Geographic locations –Hotspots based on sexual networks Different Rates of new infections per year (global) –HIV: 2.5 million –STIs: 340 million Associated mortality rates per year –HIV: 2 million –STIs: HPV: 274,000 per year, (WHO 2007), others? Transmission efficiency per coital act –HIV: 0.0082 in acute infection –STIs: CT, NG: >0.4

9. HIV Transmission efficiency: Meta- analysis of 43 observational studies Boily, MC et al 2009

10. Risk of Events Per Single Act of Unprotected Intercourse Sources: Anderson (1999); Wilcox (1995) 0 10 20 30 40 InfectionPregnancy Gonorrhea,Syphilis Chlamydia HIV (if co factors) Peri ovulatory 4-5 days pre ovulation During menses Risk Per Coital Act 50

11. Estimated Risks from 2 Acts of Unprotected Intercourse Per Week Jan. April JulyOct.Dec. SyphilisGonorrhea Chlamydia Pregnancy HIV (if cofactors) MONTHS

12. Morbidity and mortality comparison HIV OIs Metabolic complications of ART Co-morbidities Increased mortality

13. Morbidity and mortality comparison HIV Non-curable Morbidities: – OIs –Metabolic complications of ART –Co-morbidities Increased mortality STIs Curable: syphilis, NG, CT, BV, TV, chancroid Non-curable: HSV, HPV Morbidities: neonatal infections, infertility, ectopic pregnancy Mortality: HPV and cervical cancer

14. Approaches to HIV and STI prevention: brief summary of available efficacy data

15. Condoms—male and female Male condoms STIs –M acquisition: NG (Hooper 1978) –M & F acquisition: HSV-2, CT, syphilis (Holmes, 2004) –F acquisition: NG, ?TV, not HPV (Holmes, 2004) –F acquisition: HPV reduced (Winer 2006) HIV acquisition: – M & F: reduced by 80% (Weller 2002)

16. Condom Efficacy – Philippines Study Design:RCT of antibiotic prophylaxis in naval seamen on shore leave Participants:- Placebo group - Sex workers (18% gonorrhea) Questionnaire:Sexual behaviors on leave Outcome:Gonorrhea/NGU Source: Hooper, 1978, AJE

17. Condom Efficacy – Gonorrhea and NGU Condom Use Number exposed Number infectedRate Users2900.0* Non-users4985110.2% Total527519.6% * p<0.05 by Fisher’s, 1-tailed test Source: Hooper, 1978; Cates and Holmes, 1995

18. Risk of HIV Transmission, By Consistency of Condom Use, Discordant Couples 0.9 5.1 6.5 0 1 3 5 7 AlwaysSometimesNever Source: Davis and Weller (1999) HIV Incidence/ 100 PY “Consistent” “Nonuse”“Inconsistent”

19. Condoms—male and female Female condoms –STIs: Trich., CT, GC -- mixed results but probably as effective as male condoms –HIV: ? –Pregnancy: 18-21% pregnancy/12 months of typical use vs 85% historical control

20. Male circumcision HIV incidence Men: –Female-to-male HIV transmission: reduced by 50-76 percent Women : –MC of HIV+ male n ot protective for F partners

21. Male circumcision HIV incidence Men: –Female-to-male HIV transmission reduced by 50-76 percent Women : –MC of HIV+ male n ot protective for F partners STI incidence Men –no protection from NG, CT, (Sobngwi-Tambekou J, 2009) –MSM: no final word (Millet ) Tobian 2009: –HSV-2 and HPV: protective –Syphilis: not protective Women –Observational: No protection NG, CT, TV (Turner AN 2008)

22. Efficacy of STI interventions: 3 Community-level RCTs Mwanza (Grosskurth 1995) : (n =1 2,000) Improved STI case management for symptomatic STIs vs routine care; evolving HIV epidemic Rakai (Wawer 1999) : (n =14,000) Intensive STI control w/mass antibiotics vs MVI asympt. STIs q 10 mo x 3; HIV epidemic stable Masaka (Kamali 2003) : (n =20,000) Information/education (I/E) alone vs I/E + STI interventions vs routine services; HIV epidemic stable

23. Efficacy of STI Interventions Impact on HIV rates Mwanza trial –38% reduction Rakai trial –No impact Masaka trial –No impact

24. Efficacy of STI Interventions Impact on HIV rates Mwanza trial –38% reduction Rakai trial –No impact Masaka trial –No impact Impact on STI rates Mwanza trial –Syphilis rel risk 0.7 –[GC, CT, urethritis: NS] Rakai trial –Syphilis 20% ↓ prev ratio –TV 40% ↓ prev ratio –[GC, CT, urethritis: NS] Masaka trial –GC rate ratio 0.29 –Syphilis rate ratio 0.53 –[CT: NS]

25. Microbicide Strategies Initial Strategies Physical disruption of virus: Surfactants Boost normal microflora: Acidifying Agents Prevent viral entry: Sulfated Polyanions Recent Strategies Prevent replication cycle: Antiretroviral agents (NRTIs, NNRTIs) Prevent viral entry: Entry inhibitors (CCR5 inhibitors) Specificity

26. Microbicides: Surfactants HIV activity Nonoxynol-9 –Not protective C31G/Savvy –2 trials stopped for futility –Nigerian data: no efficacy at 12 months Sodium laurel sulfate (Invisible Condom) –Phase II/III planned

27. Microbicides: Surfactants HIV activity Nonoxynol-9 –Not protective C31G/Savvy –2 trials stopped for futility –Nigerian data: no efficacy at 12 months Sodium laurel sulfate (Invisible Condom) –Phase II/III planned STI activity Nonoxynol-9 –Not protective in 12 RCTS against GC, CT, TV C31G/Savvy –in vitro CT, HSV –Ph III: no protection from CT, BV, Trich, candida Sodium laurel sulfate (Invisible Condom) –Theoretical protection

28. Microbicides: Acidifying Agents HIV BufferGel –no protection (HPTN 035) Acidform/Amphora –?

29. Microbicides: Acidifying Agents HIV BufferGel –no protection (HPTN 035) Acidform/Amphora –? STIs BufferGel –HSV2, CT, HPV in animal models –No STI protection (HPTN 035) Acidform/Amphora –NG, CT in vitro –NG and CT efficacy trial planned

30. Microbicides: Viral Entry Inhibitors Sulfated Polyanions HIV PRO2000 0.5% –30% efficacy trend (HPTN 035) Carraguard –no protection (3.3 vs 3.8/100PY) Cellulose Sulfate –No protection 5.29 vs 3.33/100 PY, HR 1.61 [0.86-3.01]

31. Microbicides: Viral Entry Inhibitors Sulfated Polyanions HIV PRO2000 0.5% –30% efficacy trend (HPTN 035) Carraguard –no protection (3.3 vs 3.8/100PY) Cellulose Sulfate –No protection 5.29 vs 3.33/100 PY, HR 1.61 [0.86-3.01] STIs PRO2000 0.5% –in vitro: NG, CT, HSV –Ph III: No STI protection Carraguard –In vitro: HSV2, NG, HPV –Ph III: no STI protection –low adherence Cellulose Sulfate –In vitro: NG, CT, HPV, BV –Ph III, no NG, CT protection; –? adherence

32. Microbicides: Viral Entry Inhibitors CCR5 Inhibitors HIV PSC-RANTES –SHIV activity CMPD167 –SHIV activity with addition of two other peptides STIs –No activity expected

33. Microbicides: Reverse transcriptase inhibitors HIV Tenofovir –CAPRISA 004 Ph Iib ongoing –VOICE Ph III planned TMC120 –Ph III planned UC781 –Ph I trials ongoing STIs –No activity expected

34. Microbicide Strategies Initial Strategies Physical disruption: Surfactants Boost normal microflora: Acidifying Agents Prevent viral entry: Sulfated Polyanions Recent Strategies Prevent replication cycle: Antiretroviral agents (NRTIs, NNRTIs) Prevent viral entry: Entry inhibitors (CCR5 inhibitors) Specificity Toxicity

35. PrEP: TDF vs TDF + FTC No or limited STI activity expected

36. ART for HIV prevention Observational studies –ART reduced HIV transmission risk and high risk sex among 2993 discordant couples in Rwanda and Zambia: HR for HIV if ART used 0.21 [0.09-0.52] (P. Sullivan, CROI 2009) RCT: HPTN 052 Enrolling now –HIV incidence as 1 o endpoint, STI rates as 2 o Test and Treat concept

37. Conclusions Why do STIs get lost in the discussion on HIV prevention? –STI intervention trial results (Mwanza, Rakai, Masaka) –Microbicides: lack of STI efficacy and increasingly HIV-specific agents –Critical linkage between STI prevention and HIV prevention : may not exist

38. Conclusions Best reasons to prevent STIs –prevent STI morbidity (infertility) –minimize STI mortality (e.g., cervical cancer) How to focus on STI prevention? Condoms, STI services, HPV vaccine