1. Optimism or pessimism in microbicides research? Anatoli Kamali MRC/UVRI Uganda Research Unit on AIDS

2. Introduction Microbicides: products designed for topical application (vaginal or rectal) to reduce HIV/STIs Microbicides: products designed for topical application (vaginal or rectal) to reduce HIV/STIs Women at higher risk of HIV infection Women at higher risk of HIV infection –transmission dynamics –inability to negotiate safer sex e.g. condoms –condoms infrequently used among couples – desire to conceive Microbicides viewed as a Female controlled method Microbicides viewed as a Female controlled method

4. “Female-controlled” concept Advantages: Advantages: –self insertion before sex –could be left in place after sex –effective for multiple intercourses –men “unaware” and no consent required –potentially prevent other STIs –increase sexual pleasure

5. APPLICATION INSTRUCTIONS X X

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7. Role of men in microbicides Microbicide gel also increase sexual pleasure in men – in communities where “dry sex” is not popular Microbicide gel also increase sexual pleasure in men – in communities where “dry sex” is not popular A role in stable relationships e.g discordant couples A role in stable relationships e.g discordant couples

8. Acceptability studies

9. Safety and acceptability studies

10. Summary of findings Carraguard: safe and acceptable among Thai women up to x4/week with or without sex warranting phase III efficacy trial Carraguard: safe and acceptable among Thai women up to x4/week with or without sex warranting phase III efficacy trial PRO 2000 (0.5% and 2%): safe and well tolerated, justifying large-scale effectiveness trials PRO 2000 (0.5% and 2%): safe and well tolerated, justifying large-scale effectiveness trials

11. Safety and acceptability of penile applications BufferGel and PRO 2000 Gel daily (7 days) application to the penis BufferGel and PRO 2000 Gel daily (7 days) application to the penis –safe and well tolerated among healthy low- risk men and HIV-positive men (Stephens et al. JAIDS: 2003;33:476-83) Acceptable safety profiles Acceptable safety profiles

12. Encouraging safety and acceptability data both in women and men justifying large- scale efficacy trials in various populations Encouraging safety and acceptability data both in women and men justifying large- scale efficacy trials in various populations Optimistic that efficacy trials would show protection Optimistic that efficacy trials would show protection

13. Three generations of Microbicides 1 st generation: Nonoxynol-9 and Savvy 1 st generation: Nonoxynol-9 and Savvy –Surfactants disrupt microbial cell membranes –Vaginal defence enhancers (BufferGel)- maintain or boost the acidity of the vagina 2 nd generation: (PRO2000, Carraguard, CS) 2 nd generation: (PRO2000, Carraguard, CS) –entry inhibitors block cellular receptors and prevent HIV from attaching to and infecting target cells 3 rd generation: ARV-based (tenofovir gel, dapivirine, and UC-781) 3 rd generation: ARV-based (tenofovir gel, dapivirine, and UC-781) – prevent HIV from replicating once inside a cell

14. First generation products No effect on HIV transmission No effect on HIV transmission Nonoxynol-9: Evidence of toxicity that enhanced HIV transmission particularly among frequent users of gel (Lancet 2002; 360: 971–77) Nonoxynol-9: Evidence of toxicity that enhanced HIV transmission particularly among frequent users of gel (Lancet 2002; 360: 971–77)

15. Second generation products Cellulose sulphate: A high rate of HIV acquisition - 25cs/16p 1.61 [0.86-3.01] (N Engl J Med 2008; 359: 463-72) Cellulose sulphate: A high rate of HIV acquisition - 25cs/16p 1.61 [0.86-3.01] (N Engl J Med 2008; 359: 463-72) Carraguard: No effect on HIV transmission 134c/151p 0.89 [0.7-1.13] Lancet 2008; 372: 1977–87 Carraguard: No effect on HIV transmission 134c/151p 0.89 [0.7-1.13] Lancet 2008; 372: 1977–87

16. Summary No effect on HIV/STI transmission No effect on HIV/STI transmission Evidence of toxicity and increased risk of transmission with some products Evidence of toxicity and increased risk of transmission with some products “Worrying findings” to scientists, advocacy groups, policy makers and funding “Worrying findings” to scientists, advocacy groups, policy makers and funding

17. HPTN 035 Phase II/IIB trial 4 arm trial in 4 African countries and USA 4 arm trial in 4 African countries and USA PRO 2000 gel, buffer gel, placebo gel and no gel arm PRO 2000 gel, buffer gel, placebo gel and no gel arm

18. HPTN 035 results Presented at CROI 2009; AIDS 2011; 25:957-66 Presented at CROI 2009; AIDS 2011; 25:957-66 HIV incidence rates: HIV incidence rates: –PRO2000: 2.7 [1.9-3.7]; –Buffer gel: 4.1 [3.1-5.4] –Placebo: 3.9 [2.9-5.1]; No gel: 4.0 [3.0-5.3] PRO2000 gel: HR 0.70 [0.46-1.08], p=0.10 PRO2000 gel: HR 0.70 [0.46-1.08], p=0.10 Buffer gel HR: 1.10 [0.75-1.62], p=0.63 Buffer gel HR: 1.10 [0.75-1.62], p=0.63

20. HPTN 035 PRO 2000 trial results “The results on PRO2000 are a ray of hope for women“ “The results on PRO2000 are a ray of hope for women“ “A glimmer of hope for a possible proof of concept” “A glimmer of hope for a possible proof of concept” “MDP 301 should help refine estimate of how effective PRO2000 actually is, x 3 number of women, will yield an even more precise estimate of effectiveness” “MDP 301 should help refine estimate of how effective PRO2000 actually is, x 3 number of women, will yield an even more precise estimate of effectiveness”

21. MDP 301 trial HIV-negative women A phase 3 trial (2005- 2008), enrolled 9385 at 13 clinics, at 6 research centres in four African countries under the MDP A phase 3 trial (2005- 2008), enrolled 9385 at 13 clinics, at 6 research centres in four African countries under the MDP

22. MDP 301 trial Efficacy and safety of 0.5% and 2% PRO 2000 gels Efficacy and safety of 0.5% and 2% PRO 2000 gels Feb 2008, IDMSC stopped the 2% gel arm (futility) Feb 2008, IDMSC stopped the 2% gel arm (futility) Recommended 0.5% gel arm to continue Recommended 0.5% gel arm to continue

23. 0.5% PRO 2000 gel Incidence 4.5 [3.8-5.4]; placebo 4.3 [3.6- 5.2], HR 1.05 (0.82-1.34) Incidence 4.5 [3.8-5.4]; placebo 4.3 [3.6- 5.2], HR 1.05 (0.82-1.34)

24. Why lack of efficacy of PRO 2000 gel? Well demonstrated anti-HIV activity in preclinical studies Well demonstrated anti-HIV activity in preclinical studies Post coital diminished anti-viral activity (PD) and lower concentrations (PK) of PRO 2000 gel (Keller PLoS ONE 2010;5:e8781) Post coital diminished anti-viral activity (PD) and lower concentrations (PK) of PRO 2000 gel (Keller PLoS ONE 2010;5:e8781) –Semen, cervico-vaginal secretions and sex activity Lower concentration of products in vagina and mucosa than predicted Lower concentration of products in vagina and mucosa than predicted

25. Next generation microbicides ARV-based microbicides offer optimism ARV-based microbicides offer optimism 1% Tenofovir gel 1% Tenofovir gel Dapivirine gel and ring Dapivirine gel and ring Maraviroc Maraviroc

26. 1% Tenofovir gel acceptability Kenneth et al, AIDS 2006; 20:543-51 Kenneth et al, AIDS 2006; 20:543-51 –2-week course of 1% tenofovir vaginal gel 2x daily was well tolerated in sexually abstinent and sexually active HIV-negative and HIV- positive women Rosen et al. J Women’s Health 2008; 17: 383-92 Rosen et al. J Women’s Health 2008; 17: 383-92 –Tenofovir gel among women in a Phase I Trial was well acceptable to almost all users

27. CAPRISA-004 1% tenofovir gel – coitally dependent regimen (BAT24) 1% tenofovir gel – coitally dependent regimen (BAT24) HIV: overall 39% reduction (6-61%, p=0.017) HIV: overall 39% reduction (6-61%, p=0.017) HSV-2: 51% reduction (95% CI 22%-70%, p=0.003) HSV-2: 51% reduction (95% CI 22%-70%, p=0.003) “Proof of concept”, an exciting milestone and historic results! “Proof of concept”, an exciting milestone and historic results!

28. CAPRISA 004 effectiveness by adherence High adherers (>80% gel use): 54% lower, p=0.025 High adherers (>80% gel use): 54% lower, p=0.025 Intermediate (50-80% gel use): 38% lower, p= 0.34 Intermediate (50-80% gel use): 38% lower, p= 0.34 Low (< 50% gel use): 28% lower, p=0.30 Low (< 50% gel use): 28% lower, p=0.30 Need to achieve high Tenofovir vaginal concentrations Need to achieve high Tenofovir vaginal concentrations

29. Post CAPRISA 004 WHO/UNAIDS meeting – priority next steps WHO/UNAIDS meeting – priority next steps –Additional safety studies e.g among young women –FACTS trial to confirm findings (same regimen) –Simplified dosing and less frequent HIV testing (MDP 302)

30. FACTS 001, South Africa Phase III testing 1% tenofovir gel, same regimen as CAPRISA 004 Phase III testing 1% tenofovir gel, same regimen as CAPRISA 004 Launched October 2011 and results expected 2014 Launched October 2011 and results expected 2014

31. MTN-003 (VOICE) Safety and effectiveness among women Safety and effectiveness among women Daily 1% Tenofovir gel, oral Tenofovir and Truvada once a day Daily 1% Tenofovir gel, oral Tenofovir and Truvada once a day  Oral tenofovir and gel safe but not effective against HIV transmission  Oral Truvada arms continues, late 2012  “Disappointing findings and a large blow to the HIV prevention field!”

32. Conflicting CAPRISA and VOICE results Same product 1% Tenofovir Same product 1% Tenofovir Different dosing regimen daily vs BAT24 Different dosing regimen daily vs BAT24 Possible explanations, but no answers yet Possible explanations, but no answers yet –Adherence levels –Drug levels in genital tract –Risk behaviours of trial participants –Will be available at end of VOICE trial

33. Other microbicide formulations Gel formulations been mainly evaluated as “coitally-dependent” Gel formulations been mainly evaluated as “coitally-dependent” “Coitally –dissociated” formulations – offer sustained delivery (IVR, injectable, implants) “Coitally –dissociated” formulations – offer sustained delivery (IVR, injectable, implants) –IVR most advanced of all

34. Why a ring? Long-acting: monthly or longer Long-acting: monthly or longer –improve adherence, hence better effectiveness Easy to use, comfortable Easy to use, comfortable –Flexible ring, can be self-inserted –Rarely felt by women or their male partners –Little or no impact on sexual activity Suitable for developing world Suitable for developing world –low manufacturing cost –Good safety and acceptability data Potential for drug combinations Potential for drug combinations

35. Rectal microbicides Anal sex is a risk factor for HIV infection in both men and women Anal sex is a risk factor for HIV infection in both men and women Rectal mucosa different from the vagina and more vulnerable to HIV Rectal mucosa different from the vagina and more vulnerable to HIV –single cell layer thick; contains many more CD4 receptors; more alkaline pH which is less protective than the acidic vaginal pH Rectal tract has greater surface area Rectal tract has greater surface area

36. the Future …. Requires both vaginal and rectal products Requires both vaginal and rectal products Research is required to find the right drug at the right and in the right place Research is required to find the right drug at the right and in the right place Require a lot of support from funding agencies Require a lot of support from funding agencies ARV-based combination products ARV-based combination products Challenges: drug toxicity, resistance Challenges: drug toxicity, resistance

37. Combination Microbicides Advantages: Advantages: –Potential increased efficacy –Potential synergy and need for less drug Possible disadvantages Possible disadvantages –Difficulties in co-formulation –Increased cost –Potential for toxicity and resistance

38. Combination Microbicides Various combinations in development Various combinations in development –Dapivirine/Tenofovir ring –Dapivirine/Maraviroc gel, film and ring form

39. Conclusions Data supports that high gel and condom use Data supports that high gel and condom use –Gel: 96.2% Carraguard, 95.9% placebo –Condom: 64·1% in both groups at last sex –MDP 301, mean reported gel use was 89% and condom 55-57% ? Consistent gel use in real world ? Consistent gel use in real world

40. Conclusions More potent ARV-based products and new formulations More potent ARV-based products and new formulations Long term effects of IVR Long term effects of IVR –could disturb the vaginal environment and increase HIV acquisition risk? Need to keep major donors interested and political will Need to keep major donors interested and political will Optimistic that a microbicide dream will be a reality and turn the HIV epidemic in women and men Optimistic that a microbicide dream will be a reality and turn the HIV epidemic in women and men

41. Optimistic A dream to a reality of a safe, effective and affordable microbicide A dream to a reality of a safe, effective and affordable microbicide “All our dreams can come true, if we have the courage to pursue them” “All our dreams can come true, if we have the courage to pursue them” Together we can turn the HIV epidemic in women and men Together we can turn the HIV epidemic in women and men

42. Acknowledgements Funders: MRC (UK), DFID, other agencies Funders: MRC (UK), DFID, other agencies Allan Stone, Annalene Nel, Elizabeth Bukusi, Janneke van de Wijgert and Sheena McCormack Allan Stone, Annalene Nel, Elizabeth Bukusi, Janneke van de Wijgert and Sheena McCormack