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Rectal microbicides

Rectal microbicides. An update Gus Cairns. Why now?. Alternatives to condoms needed Incidence in gay men is not going down Vaginal microbicides may be available within two years Safety concerns – and not just among gay men Human trials – at last – about to start.

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Rectal microbicides

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  1. Rectal microbicides An update Gus Cairns

  2. Why now? • Alternatives to condoms needed • Incidence in gay men is not going down • Vaginal microbicides may be available within two years • Safety concerns – and not just among gay men • Human trials – at last – about to start

  3. Alternatives to condoms needed • UK • Gay HIV prevalence in London2000, anon testing: 12.8%. • GMSS, data collected 2004: 6.5% UK-wide, 13.2% London • Among STD clinic attendees, London, 2005: 20.3% • USA: • Annual incidence, anon testing: white gay men, Baltimore: 3%. Black gay men: 15% • Asia: • MSM, Bangkok: prevalence, anon testing: 2003, 17%. 2005, 28%.

  4. Gay men try to protect themselves • Serosorting study, Seattle: • HIV diagnoses among men who: • “Did not have anal sex”: 0.9% • “Did not have UAI”: 1.5% (34% of testees) • “Only had UAI with other negative guys”: 2.6% • Took no precautions: 4.0% • About one in five gay men who have UAI try only to do it with concordant partners

  5. Latest London gym study

  6. …but appears to have no effect on incidence HPA anonymous testing programme, gay men attending STD clinics

  7. We need biomedical interventions because: • They don’t rely on perceptions of risk • They don’t require disclosure • They could possibly be used well in advance of sex – of, if not, in a way that adds to pleasure • They don’t rely on you preparing your ‘works’ when you’re ‘high’ • They’re compatible with sexual dysfunction • The more prevention tools we have the more they can be used ‘in combination’

  8. Demand: Do Gay Men Want a Rectal Microbicide? Terrence Higgins Trust 2003 Gay Men’s sex survey

  9. An example of a successful biomedical intervention • Circumcision study, South Africa, 2005 • Reduced acquisition of HIV in circumcised men by 75% • Cohort study, Uganda, 2006 • Female partners of circumcised men had 30% lower rate of HIV infection (and some STDs) • Where’s the gay men’s study….?

  10. …and is catching on SWAZILAND: Circumcision Makes Comeback in AIDS-Hit Swaziland Rebecca Harrison Reuters (02.24.06) - Tuesday, February 28, 2006 Circumcision has recently gained high regard in Swaziland in the wake of the first controlled study to show that circumcised men are about 60 percent less likely to contract HIV. French and South African scientists reported the findings, first published in the Public Library of Science Medicine, which quickly filtered into Swazi media. In the capital recently, patients eager to undergo the procedure almost rioted at an overbooked clinic where it is performed. "There was a stampede," said Dr. Mark Mills, administrator at the private Mbabane Clinic. "There is not a family in Swaziland unaffected by HIV, and people are desperate." Swazi mothers are a key factor in promoting circumcision. "I decided he needed to do it for safety and for the future," said Phindile Maseko, a nurse at Mbabane whose 13-year-old son was circumcised. "Swazi men have heard that it is a good thing and when you play with your partner the sex is good," said Titus Shabangu, 36, who was recently circumcised. "That is why they come." • SWAZILAND: Circumcision Makes Comeback in AIDS-Hit Swaziland • Reuters (02.24.06) - Tuesday, February 28, 2006 • Circumcision has recently gained high regard in Swaziland in the wake of the first controlled study to show that circumcised men are about 60 percent less likely to contract HIV. In the capital recently, patients eager to undergo the procedure almost rioted at an overbooked clinic where it is performed. • "There was a stampede," said Dr. Mark Mills, administrator at the private Mbabane Clinic. "There is not a family in Swaziland unaffected by HIV, and people are desperate." • Swazi mothers are a key factor in promoting circumcision. "I decided he needed to do it for safety and for the future," said Phindile Maseko, a nurse at Mbabane whose 13-year-old son was circumcised. • "Swazi men have heard that it is a good thing and when you play with your partner the sex is good," said Titus Shabangu, 36, who was recently circumcised. "That is why they come." • The Mbabane Clinic is performing 10 circumcisions weekly, up from less than one a month prior to the study.

  11. …and another one (at least in monkeys) • PREP study, CROI 2006 • Monkeys given tenofovir/FTC and then rectally challenged with SHIV • 0/6 infected • In control group 5/6 infected • 1/6 infected when FTC was used alone • Safety study (400 men) in USA ongoing • Efficacy study (1200 men) in Peru [finally] soon to start. Results: 2009.

  12. US PREP trial

  13. …and is catching on • Study presented at IAS Conference, Rio, 2006 • People interviewed at gay festivals in Oakland, San Francisco, Baltimore, Detroit – only 75% of them gay/bisexual • 25% had heard of PREP • 7% had taken it – 9% in SF

  14. Microbicides • Creams, gels, enemas, or slow-release devices that: • 1st generation: • Place a barrier between HIV and mucosal cells (1st generation) • Disrupt viral membranes (safety considerations – N9) • Change pH of body cavities (Similar safety worries) • 2nd generation: • Contain antiretroviral drugs (TMC120, UC781, tenofovir) • And/or contain more sophisticated barrier chemicals/fusion inhibitors (cyanovirin-N) • 3rd generation: • Combination approaches plus genetic therapies (modified gut bacteria, etc)

  15. Vaginal studies

  16. Timelines… • Carraguard/Population Council/Gates: Jan 2008 • Cellulose sulfate/CONRAD/USAID: September 2008 • PRO2000/MRC: March 2009

  17. Anal sex is heterosexual too

  18. Rectal microbicides… • More of a design and research challenge because… • Less politically attractive for funders • Rectum/colon much more receptive to HIV so first-generation vaginal Mics. might not work • Also more fragile so increased safety issues • Coverage problem – large area so what formulation would work?

  19. Mucosal Transmission of HIV Infection Shattock and Moore 2003

  20. Why volume is an issue… Without Coital Simulation With Coital Simulation 10 mL HEC gel (1:100 Gadolinium [Gd] label for MRI), subject supine B-bladder; SP-symphysis pubis; RA-rectal ampulla; A-anus; L5-5th lumbar vertebra; S1-first sacral vertebra.

  21. …or, a little goes a long way Fourth Hour Post-Dose (1139 HRS) “Concentration” SPECT / CT Fusion First Hour Post-Dose (0803 HRS) SPECT / CT Fusion “Concentration” Subject F003: Coital simulation with 5 mL semen simulant @ 0734 HRS CT: Gray scale SPECT: color scale

  22. What’s happened so far • Monkey studies • Toxicity studies • Acceptability studies

  23. Proof-of-concept: Cyanovirin-N Tsai et al. 2003

  24. Toxicity studies • We know virtually nothing about how gay men use LUBES or whether they are toxic • Exception: nonoxynol-9 • David Phillip, Population Council assessing safety of 13 lubes: results ready for Microbicides 2006

  25. Cytotoxicity

  26. Rectal protection – mice and HSV-2

  27. Cell-sloughing (damage to rectum) 10 9 8 7 6 5 4 3 2 1 0 Number cells/ml (1 x 108)

  28. Acceptability study - solo

  29. Acceptability study – in sex

  30. Laboratory Testing 2-6 Years Phase 1 1 Year Phase 2 2 Years Phase 3 3.5 Years Phase 1 and 2 penile and rectal studies, HIV+, etc. 10 + Years Current microbicide development times Source: Tufts Center for the Study of Drug Development

  31. UC-781 study

  32. Why we need community preparedness NOW

  33. Thanks to: • Ian McGowan, Co-Director, UCLA Center for HIV & Digestive Diseases • Craig W. Hendrix, Associate Professor of Medicine, Johns Hopkins University School of Medicine • Alex Carballo-Diéguez, Associate Professor of Clinical Psychology, HIV center for clinical and behavioural studies, Columbia University • Robin Shattock, Reader in Cell Biology of Infection, St George’s Hospital Medical School, London • David M Phillips, Population Council, New York • Alan Stone, Chair, International Working Group on Microbicides • Caroline Haworth, Director of International programmes, InterACT Worldwide • Albert Liu, HIV Research Section, San Francisco Department of Public Health

  34. And… • Kim Mulji, Executive Director, Naz Foundation International

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