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RECTAL MICROBICIDES RESEARCH CURRENT STATUS & CHALLENGES

RECTAL MICROBICIDES RESEARCH CURRENT STATUS & CHALLENGES. Dr. Badri N. Saxena, M.D., F.A.M.S. Professor, Centre for Policy Research, New Delhi Advisor, Indian Council of Medical Research, New Delhi Rectal Microbicides Advocacy November 29, 2006. RECEPTIVE ANAL INTERCOURSE (RAI).

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RECTAL MICROBICIDES RESEARCH CURRENT STATUS & CHALLENGES

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  1. RECTAL MICROBICIDES RESEARCH CURRENT STATUS & CHALLENGES Dr. Badri N. Saxena, M.D., F.A.M.S. Professor, Centre for Policy Research, New Delhi Advisor, Indian Council of Medical Research, New Delhi Rectal Microbicides Advocacy November 29, 2006

  2. RECEPTIVE ANAL INTERCOURSE (RAI) • RAI is a risk factor for HIV infection for both men and women • LACK OF RELIABLE DATA in India and globally • 30% heterosexuals in some cultures engage in RAI • Sex workers and women with substance abuse more vulnerable • Total volume and numbers of unprotected RAI is 5 times higher in heterosexuals as compared to MSM • THUS BOTH WOMEN AND MEN NEED RECTAL MICROBICIDES

  3. HIV PREVENTION TECHNOLOGIES • Condom effective but not sufficient • Need another technology e.g. microbicides • Potential impact of Rectal microbicides Mathematical modeling by UCLA group 50% effective microbicide used in 50% of RAI would reduce the new infection by 13%

  4. Current status • Very few human studies to date and published studies only on N-9 • Several vaginal products have been evaluated in pig-tailed macaque model by Dorothy Patton • Nonoxynol-9 found to be profoundly toxic in this model (Sexually Transmitted Disease, 2002, 29:581) • Investigators still trying to figure out “how” to conduct and evaluate phase I studies appropriately

  5. Basic Colorectal Anatomy Length of colorectal column: 30 feet!

  6. Physiological Differences

  7. What happened to N-9? • Work with N-9 as a potential microbicide ceased • CDC issued guidance saying that N-9 should not be recommended for HIV prevention or included in “hierarchical” messages and N-9 lubricated condoms should no longer be recommended • WHO advised against N-9 for disease prevention. N-9 only recommended as a contraceptive option for women not at risk of HIV

  8. Nonoxynol-9 and rectal sex • David Phillips, et al. found that even low doses of N-9 caused massive sloughing of the rectal epithelium (n=4 people). Findings duplicated in large sample • Rectal epithelium heals quickly – less than 8 hours • Damage associated with rectal use of N-9 is far more extensive than observed with vaginal use of products • Rectal exposure to N-9 increases transmission of HSV in mice and monkeys

  9. Gay men are still seeking out N-9 • Among a diverse sample of 573 MSM in San Francisco, 67% had used N-9 in the past year • This was after CDC issued warnings and the San Francisco DOH undertook outreach activities • Among those who had used N-9 in the last year: • 41% used it without a condom because they thought the N-9 might be protective

  10. ONGOING RESEARCH: PRE-CLINICAL ASPECTS • Which elements of intestinal mucosa are the initial targets of HIV infection? Which regions of colon need safeguarding ? • Semen simulant can travel 2-3 feet into colon. How to deliver rectal microbicides ? Foams / enemas / suppositories ? • What are the biomarkers for safety testing – in vitro / in vivo systems • Proof of concept: Macaque model for SHIV / SIV infections (CVN study) • Minimum effective dose/ bioavailability / distribution • Ongoing discussion about whether rectal safety testing should be done for all vaginal microbicides

  11. ONGOING RESEARCH: BEHAVIOURAL RESEARCH • Sexual behavioral studies amongst women and men engaged in RAI • User acceptability of rectal microbicides • Use of products on a continued basis

  12. Research in action Laboratory studies: Dr. Ian McGowan, HPTN 056, University of California/Los Angeles Defining measurements that can be made on rectal tissue biopsies that would be of use in rectal microbicide safety studies. Distribution studies: Dr. Craig Hendrix at Johns Hopkins University, MD • Volunteers simulated anal intercourse • MRI scans done up to five hours after its release • Initial studies suggest that semen could travel up to 60 centimeters • Showed where a microbicide would be needed to protect vulnerable tissues

  13. Behavioral research in action: Alex Carballo-Diéguez, Columbia Univ,NY Ken Mayer, Fenway Community Health, Boston Maximum acceptable dose for insertion and anal Intercourse Alex Carballo-Diéguez & Sigma Research Center Surveys of MSM interest in using microbicide • San Francisco: 59% heard of microbicides, 25%-35% might use (depending on stated effectiveness) • UK: 23% had heard of microbicides, 59% might use

  14. ONGOING RESEARCH: CLINICAL ASPECTS PHASE 0 • Baseline studies of injury and inflammation in rectum amongst men and women during typical RAI • Male tolerance: Penile and urethral irritation of potential Rectal Microbicide

  15. ONGOING RESEARCH : CLINICAL TRIALS PHASE 1 Safety studies • RTI product: PMPA / a form of Tenofovir • NNRTIs: TMC 120-Dapvirin , UMC 781 • Entry Inhibitors: Pro-2000 • Dendrimer polyanion; VivaGel • All vaginal microbicides to be studied

  16. Patton rectal safety study summary

  17. Patton rectal safety study summary

  18. Rectal Safety of Vaginal Microbicides

  19. Rectal microbicides expenditures: 2000-2006

  20. THANK YOU

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