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

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%.

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

Latest London gym study

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

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’

Terrence Higgins Trust 2003 Gay Men’s sex survey >10,000 from web Heard ofWould consider PEP21%71% Home HIV test 22%53% Microbicide23%59% Vaccine66%50% Demand: Do Gay Men Want a Rectal Microbicide?

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….?

…and is catching on SWAZILAND: Circumcision Makes Comeback in AIDS-Hit Swaziland Reuters ( ) - 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. SWAZILAND: Circumcision Makes Comeback in AIDS-Hit Swaziland Rebecca Harrison Reuters ( ) - 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."

…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.

US PREP trial

…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

Microbicides Creams, gels, enemas, or slow-release devices that: 1st generation: Place a barrier between HIV and mucosal cells (1 st 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) 3 rd generation: Combination approaches plus genetic therapies (modified gut bacteria, etc)

Vaginal studies

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

PopulationNPrevalence of AI Reference MSM in EXPLORE study – 54%Koblin et al High risk women %Gross M et al College students 21020%Civic D 2000 Californian residents %Erickson PI et al Anal sex is heterosexual too

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?

Shattock and Moore 2003 Mucosal Transmission of HIV Infection

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; L5-5 th lumbar vertebra; S1-first sacral vertebra.

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

What’s happened so far Monkey studies Toxicity studies Acceptability studies

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

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

Cytotoxicity Compounds Dilution (50% Cytotoxicity) MethylcelluloseNon cytotoxic (1:1) CarraguardNon cytotoxic (1:1) Viamor1:1 Vagisil1:5 Astroglide1:32 Delube1:140 KY- Plus1:330

Rectal protection – mice and HSV-2

Cell-sloughing (damage to rectum) Number cells/ml (1 x 10 8 )

Acceptability study - solo

Acceptability study – in sex

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

UC-781 study

Why we need community preparedness NOW

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

And… Kim Mulji, Executive Director, Naz Foundation International