Microbicides: What will they do? What will they be like? What needs to be done? Richard A. Cone Johns Hopkins University ReProtect, LLC (“BufferGel™” & “BufferGelCup”)

What will they do? Protect mucosal surfaces (vagina, rectum) from infections because microbicides….. Kill or inactivate microbes like HIV and herpes. Most 1 st generation microbicides will be gels that lubricate,reducing discomfort and minor trauma. For even more reliable vaginal protection, microbicides may also be used with a discrete internal barrier, like a diaphragm, cap, or shield.

.. SPERM STD PATHOGENS VAGINAL FLORA CERVIX VAGINAL EPITHELIUM chlamydia syphilis gonorrhea HSV-2 HIV HPV "Trojan Horse" HIV-infected white blood cells lactobacilli  acid ~pH 4 yeast E. coli Staph. aureus  toxin many others Microbicide Should Inactivate Diverse Pathogens and Sperm Yet Not Disturb Vaginal Flora or Epithelium Mucus Layer BV flora

Types of microbicides: Some will be specific for inactivating HIV. Some will be broad spectrum and kill many germs: viruses – HIV, HSV(herpes), HPV(warts,cancer). bacteria - chlamydia, gonorrhea, syphilis. protozoa - trichomonas vaginalis. HIV-infected white blood cells in genital secretions. Some will be contraceptive microbicides that block both sperm and germs to prevent pregnancy and disease.

Mechanisms used by microbicides now being developed: 1. Kill germs: detergents (e.g. Savvy™), vaginal acidity (pH ~4) (e.g., BufferGel™). 2. Stick to germs so they can’t infect target cells: (e.g., Caraguard™; PRO2000™; dextrin sulphate). 3. Coat the vagina with a gel that germs can’t penetrate: (lubricant gels that prevent direct contact; “Liquid Condom”). 4. Inactivate HIV with specific antiretroviral inhibitors and agents that block specific HIV receptors. 5. Boost vaginal defenses: Reinforce vaginal acidity (pH ~4). Support vagina’s “good” bacteria, lactobacilli. Suppress vagina’s “bad” bacteria, BV bacteria.

Microbicides will provide woman-controlled protection: She can insert the microbicide discretely before sexual activity begins. Whether or not he uses a condom, she can still protect herself.

Unfortunately, like condoms, microbicides must be used for every act of intercourse. Not there? No protection. Fortunately, like condoms, microbicides may protect both sexual partners (Bi-directional protection).

What will they be like?

First generation products: (gels) 1) Conventional tube and reusable applicator. 2) Single dose applicators. 3) Use with a diaphragm, cap, or shield. 4) Disposable, precoated shield. Possible second generation products: 1) Vaginal ring for long-term protection. 2) Daily vaginal tablets. 3) Adjuncts: Lactobacilli that produce peroxide. Eventually: 1) Combination microbicides. 2) Vaccines? 3) “Designer” lactobacilli?

What needs to be done?

Paradox: Nonoxynol-9 (N9) is a detergent. It instantly kills both sperm and HIV, - - so N9 is a potent spermicidal microbicide. And N9 is an effective contraceptive. But unfortunately, N9 failed to prevent HIV in major clinical trials.

In animals test, for a short time after detergents like N9 are applied (<1 hour), they protect against vaginal and rectal infections. But detergents irritate mucosal surfaces far more than anyone expected. And this irritation makes the vagina and rectum more susceptible to infections for a long time after the detergent is no longer present (“post-exposure increase in susceptibility”).

In the HIV-prevention trials of N9, women used N9 frequently. When they applied N9 right before intercourse they may have been protected, but probably they were more susceptible to infection on those occasions when they didn’t use N9.

Implication: Microbicides must be extraordinarily nontoxic.

Microbicides will be subjected to many tests to be sure they are not toxic: 1. Sensitive tests for vaginal and rectal toxicity in animals. 2. If nontoxic in animals, test clinically in “Phase I” Safety Trials. 3. If nontoxic in Phase I Trials, proceed to larger “Phase II” Safety (& sometimes Efficacy) trials. 4. Finally, proceed to even larger and longer “Phase III” Efficacy and Safety trials. The FDA may approve a microbicide for marketing only if it is found safe in all these tests, and the tests must show that the microbicide is effective.

These tests take many years, and major funding, to complete. FDA regulations are not yet fully defined for microbicides: the FDA has not yet approved any microbicide. HIV tests will require the most time, the most money, and the most participants. Tests for preventing common STIs and vaginal infections (like BV) are also needed, and will require less time, money and participants.

About 60 small biotech companies and nonprofit organizations are actively developing microbicides: Today there are: 1) Over 30 microbicides in pre-clinical development. 2) About 15 in early clinical testing, 3) Several in, or scheduled for, Phase III Efficacy Trials: Sulfated polymers: (Caraguard, Pro2000, Dextrin Sulfate, Cellulose Sulphate)Vaginal Buffer: (BufferGel). Funds for developing these microbicides are supplied almost exclusively by government and foundation grants.

More funds are needed: It costs ~$10 million to develop a candidate microbicide all the way through Phase I or II trials. It costs ~ $45 million to complete one large Phase III trial. Last year, the entire NIH funding for microbicides was ~ $47 million. (Less than 2% of it’s AIDS research budget.) Government funding for microbicide R&D must scale up dramatically if the promise of microbicides is to be realized.

Some ways advocates can help: Lobby for increased funding. Stimulate interest in the media, and community. This will: 1. Increase investor support of the small biotech companies. 2. Speed clinical trials by encouraging more women to enroll. (HIV, STIs, BV) 3. Build the vanguard of women who will benefit from microbicides. Enroll in a clinical trial!