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Optimism or pessimism in microbicides research?

Optimism or pessimism in microbicides research?. Anatoli Kamali MRC/UVRI Uganda Research Unit on AIDS. Introduction. Microbicides: products designed for topical application ( vaginal or rectal) to reduce HIV/STIs Women at higher risk of HIV infection transmission dynamics

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Optimism or pessimism in microbicides research?

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  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 • 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

  3. “Female-controlled” concept • 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

  4. APPLICATION INSTRUCTIONS X X

  5. Role of men in microbicides • 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

  6. Acceptability studies

  7. Safety and acceptability studies

  8. Summary of findings • 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

  9. Safety and acceptability of penile applications • 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

  10. 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

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

  12. First generation products • 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)

  13. 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) • Carraguard: No effect on HIV transmission 134c/151p 0.89 [0.7-1.13]Lancet 2008; 372: 1977–87

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

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

  16. HPTN 035 results • Presented at CROI 2009; AIDS 2011; 25:957-66 • 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 • Buffer gel HR: 1.10 [0.75-1.62], p=0.63

  17. HPTN 035 PRO 2000 trial results • “The results on PRO2000 are a ray of hope for women“ • “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”

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

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

  20. 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)

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

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

  23. 1% Tenofovir gel acceptability • 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 • Tenofovir gel among women in a Phase I Trial was well acceptable to almost all users

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

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

  26. Post CAPRISA 004 • 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)

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

  28. MTN-003 (VOICE) • Safety and effectiveness among women • 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!”

  29. Conflicting CAPRISA and VOICE results • Same product 1% Tenofovir • Different dosing regimen daily vs BAT24 • 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

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

  31. Why a ring? • Long-acting: monthly or longer • improve adherence, hence better effectiveness • 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 • low manufacturing cost • Good safety and acceptability data • Potential for drug combinations

  32. Rectal microbicides • 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 • 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

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

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

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

  36. Conclusions • 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

  37. Conclusions • More potent ARV-based products and new formulations • Long term effects of IVR • could disturb the vaginal environment and increase HIV acquisition risk? • 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

  38. Optimistic • 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” • Together we can turn the HIV epidemic in women and men

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

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