1. National Working Group on Microbicides 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. National Working Group on Microbicides 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. National Working Group on Microbicides 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. National Working Group on Microbicides 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

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

7. National Working Group on Microbicides Physiological Differences VaginaRectum Most of the epithelium is 40 cell layers thick Very fragile epithelium, 1 cell layer thick. Fewer CD4 cells than rectumMore inflammatory cells under surface (CD4 receptors) Acidic pHAlkaline, rather than acidic pH Enclosed pouchOpen-ended tube

8. National Working Group on Microbicides 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

9. National Working Group on Microbicides 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

10. National Working Group on Microbicides 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

11. National Working Group on Microbicides 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

12. National Working Group on Microbicides 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

13. National Working Group on Microbicides 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

14. National Working Group on Microbicides 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

15. National Working Group on Microbicides 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

16. National Working Group on Microbicides 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

17. National Working Group on Microbicides Patton rectal safety study summary ProductMicroflora changesDisruption of epithelium N-9 + +++ Carraguard - - Savvy - - Vivagel - - Buffer gel - - Microbicides 2006: Poster 110

18. National Working Group on Microbicides Patton rectal safety study summary ProductMicroflora changesDisruption of epithelium Cellulose suflate - - UC781 - - Polystyrene sulfonate - - Octyglycerol - - Microbicides 2006; Poster 110

19. National Working Group on Microbicides Rectal Safety of Vaginal Microbicides CandidateMurinePrimateExplantHuman N-9+++ Buffer gelNeg ?? Savvy?Neg?? CarraguadNeg ?? Cellulose sulfate?Neg?? Pro-200??Neg? SPL 7013?Neg?? TMC 120??Neg? PMPA?Neg ? UC781Neg ? Octyglyceral?Neg??

20. National Working Group on Microbicides Rectal microbicides expenditures: 2000-2006

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22. THANK YOU