Microbicides: Where Are They Now?
One of the drawbacks of the condom is that its use may be controlled by the insertive partner -- so it can sometimes be difficult for the receptive partner to make sure that one is used. Even the female condom requires a partner's cooperation for proper use. Add to this the fact that many men don't like the feel of male condoms and that they can sometimes make it difficult to maintain an erection, and you can see why microbicides are being studied, especially when the aim is to provide women with a prevention tool they can control.
This article (adapted from information available at the Global Campaign for Microbicides) answers some of the basic questions people have about microbicides, and provides updates on the candidates that are furthest along in testing.
What is a Microbicide?
A microbicide is a substance that can reduce transmission of sexually transmitted infections (STIs), including HIV, when applied in either the vagina or rectum. A microbicide could be produced in many forms: gels, creams, suppositories, films, lubricants, or sponges or vaginal rings that slowly releases the active ingredient.
A microbicide could prevent HIV and STIs by:
Ideally, a microbicide would combine some or all of these mechanisms for extra effectiveness.
When used consistently and correctly, condoms are likely to provide better protection against HIV and STIs than microbicides, so they will still be the preferred option. But for people who cannot or will not use condoms, and particularly for women whose partners refuse condoms, microbicides could save lives and have a substantial impact on the spread of HIV. In fact, one mathematical model showed that if even a small proportion of women in lower income countries used a microbicide that was 60% effective in half the sexual encounters where condoms are not used, 2.5 million HIV infections could be avoided in just three years.
HIV, STIs, and Pregnancy
Since STIs are caused by different pathogens (some viral, some bacterial), a microbicide that works against one STI might not protect against another. Reducing HIV risk is the primary goal of microbicide research, but some of the microbicides currently being tested appear to have some efficacy against at least one other STI in addition to HIV. Eventually, a combination product that works in multiple ways could offer protection from a wide range of STIs, including HIV.
Some microbicides being studied prevent pregnancy and some do not. It's important to have both non-contraceptive microbicides and "dual-action" microbicides that prevent pregnancy and infection, so that women and couples can protect their health and still have children. This is not possible with condoms.
Trial Safety and Ethics
Any new product must go through rigorous safety testing before becoming available to consumers. Women's health activists and researchers are working closely together to ensure that the clinical testing of microbicides is thorough and ethical. Fortunately, some of the substances and mechanisms of action under investigation are already in use on other products -- so some safety data about them are available already (although their possible efficacy as microbicides is not yet proven).
Current clinical trials are studying whether microbicides could protect HIV-negative women from infection, but there is hope that some products may eventually be shown to protect men if their female partner is HIV positive. Evaluating whether a microbicide protects male partners, however, will require separate clinical trials.
Virtually all microbicide research to date has been conducted by not-for-profit and academic institutions or small biotech companies. Studies are funded by charitable foundations and government grants. These funds also support basic science, social and behavioral research, and clinical trial infrastructure that contribute to microbicide research and development. Large pharmaceutical companies have not invested significantly in this field, primarily because microbicides are a classic "public health good" that would yield tremendous benefits to society but for which the profit incentive to private investment is low.
A Failed Candidate
Until recently, two organizations were conducting separate trials of cellulose sulfate (CS), also known as Ushercell. CONRAD, a reproductive health research organization, was conducting a trial among women in Benin, India, South Africa, and Uganda, while Family Health International (FHI) was conducting a trial in two sites in Nigeria. Both sponsors are not-for profit research groups dedicated to advancing health in developing countries.
CONRAD halted its trial after early results suggested that CS might be contributing to an increased risk of HIV infection among women in the study. Even though the FHI trial did not find the same increased risk, it decided to stop its trial, choosing to err on the side of caution. There were no differences in the rates of STIs other than HIV between the two groups.
Before the CONRAD trial was stopped, 35 women had seroconverted (in both the experimental and the control groups -- we do not know yet how many were in each group). The analysis was based on small numbers and may change as more data are studied -- more women may be found to be HIV positive once all women return to the site and are tested, or it may be learned that some women received false negative HIV test results at the time of their enrollment.
Eleven safety trials on CS were conducted prior to the initiation of these Phase III trials and no differences were observed between women using the CS gel and women using placebo gel. All participants in both trials received monthly HIV prevention counseling, free condoms, and prompt diagnosis and treatment for any curable sexually transmitted infections. Extensive measures were taken at all trial sites to help women understand that they should not rely on the test product to protect them from HIV, and that half were receiving a placebo gel (known to be ineffective).
Scientists are trying hard not to speculate until more is known. It is likely to be several months before the data analysis will be completed and publicly available. In the meantime, studies of other candidates continue.
Carraguard is an attachment inhibitor that provides a physical barrier between pathogens and vulnerable cells in the cell wall (epithelium) of the vagina or rectum. It is not expected to be contraceptive, and may provide some protection against HIV, HSV, HPV, and gonorrhea. The active pharmaceutical ingredient in Carraguard is carrageenan, a substance derived from seaweed. Carrageenan is used as a thickener in foods and as an emulsifier in topical creams and lotions such as those used in the cosmetics industry.
A large trial of Carraguard, conducted by the Population Council, was completed in March of 2007, with results expected by the end of 2007 or early 2008. Carraguard is the first new microbicide to have reached completion of its Phase 3 trial.
BufferGel is an acid buffer that keeps the vagina acidic even in the presence of semen. It also creates a physical barrier that stops or slows down the passage of pathogens into the vaginal and cervical walls. It is hoped it will also work to prevent pregnancy, at the same time helping to protect against HIV, HPV, HSV, chlamydia, and gonorrhea. Buffer Gel is being studied along with PRO 2000 (below) in a large trial (HPTN 035) of 3,100 women at seven sites in Malawi, South Africa, Zambia, Zimbabwe, and Philadelphia.
In this trial, women are placing a single dose of BufferGel, PRO 2000 gel, or placebo gel into the vagina up to 60 minutes before vaginal intercourse, using single-use, pre-filled applicators. The trial also includes a "condoms only" arm in which women apply no gel at all. Everyone receives ongoing HIV risk reduction counseling, condoms, and diagnosis and treatment of sexually transmitted diseases. Results are expected in 2009.
PRO 2000 (napthalene sulphonate) is an entry and fusion inhibitor that binds to viruses and bacteria to prevent them from infecting healthy cells. Its ability to prevent pregnancy may depend on the dose used. It may help protect against HIV, gonorrhea and HSV. See above for info on current trials.
Tenofovir is an HIV drug contained in Viread, Truvada, and Atripla. It was chosen to test as a microbicide gel because it is active in many of the cells that HIV targets for infection, such as dendritic cells, macrophages, and CD4 cells. These cells are abundant in the vagina. Animal studies found that tenofovir gel prevented infection in monkeys when given before or after infusions of SIV (a virus similar to HIV).
It is being studied in HPTN 059, a six-month trial of two methods of use: either daily or only before sex. Women in the study will use either tenofovir or placebo gel, and half the women will have colposcopies (an examination of the cervix). All participants will be provided with condoms and counseled to use them. The trial is being conducted in Birmingham, Alabama; the Bronx, New York; and India. Another trial is being done in the Dominican Republic.
Several other microbicides are in early development, including dapivirine (TMC120), an HIV drug that is being studied as both a gel and a vaginal ring; lauryl sulfate ("the invisible condom"), which is liquid at room temperature but changes to a gel when applied to the body; UC-781, a drug in the same class as Sustiva that is being studied in gel form; and SPL7013 (VivaGel), which uses synthetic molecules called dendrimers to encapsulate and disable HIV. VivaGel is the only microbicide being studied for use both in the vagina and on the penis.
The few international studies available show that anal intercourse occurs all over the world -- and not only in men who have sex with men. Heterosexual couples also engage in anal sex in many cultures. In U.S. surveys, 35% of heterosexual women reported having had anal intercourse at some time in their lives and 6.7% of heterosexual couples practice anal intercourse at least once a month.
Receptive sex partners (whether women or men) are at 10 to 100 times higher risk of HIV infection than insertive partners during unprotected anal intercourse. But both partners can be exposed to other STIs, including anal warts, hepatitis B, syphilis, and gonorrhea. For those unable or unwilling to use condoms, rectal microbicides could be a safe and effective alternative means of reducing risk, especially if they were unobtrusive or enhanced sexual pleasure enough to motivate consistent use.
Although a number of microbicides are being studied for vaginal use, it's not clear yet which of them would also be suitable for rectal use. The rectum and the vagina differ significantly in many ways. The vagina, for example, is virtually a closed pouch while the rectum is part of an open-ended cavity. A greater quantity of the microbicidal product will probably be needed for adequate rectal coverage than for vaginal use. The rectal lining is more fragile than most of the tissue lining the vagina, and the rectum is also richer in the CD4 cells that are particularly vulnerable to HIV infection. Some of these factors further enhance rectal vulnerability to irritation, tearing, and infection during sex.
Some researchers have been looking at the "over-the-counter" lubricants available in pharmacies and sex shops to see if they might work as microbicides. Three of these commercial products have been shown to kill HIV in the test tube. However, commercial lubricants often contain preservatives, perfumes and other ingredients that could cause irritation if applied internally on a regular basis and/or in large quantities. Preliminary research already suggests that some lubricants are significantly more likely to cause rectal irritation than others. More research and advocacy regarding lubricant safety is urgently needed.
As we learned with nonoxynol-9 (which, after years of being recommended as possibly helpful in protecting against HIV, was found actually to increase the risk of HIV infection, and to be especially damaging to the rectum), it is dangerous to make assumptions about a product's safety or effectiveness before the research on it is complete. There is no proof that any of the available over-the-counter lubricants are either safe or effective as microbicides -- and there is evidence suggesting that some may be more irritating to rectal tissue than others.
No one strategy or technology will "solve" the AIDS pandemic. We must use all existing prevention strategies: behavior change, voluntary counseling and testing, STI diagnosis and treatment, broad access to male and female condoms, and access to sterile syringes and HIV treatment, while we work to develop new tools and technologies. Microbicides will likely be available and accessible sooner than an HIV vaccine. Even after a safe and effective vaccine is discovered, however, vaccines and microbicides will have different, complementary roles to play in a global HIV prevention strategy.
And once we find effective microbicides, it's essential that they get into the hands of women and men who need them at a price they can afford. In the past, new health technologies have rarely become widely available in developing countries until more than a decade after their approval in the U.S. and Europe, an unacceptable delay for life-saving products developed primarily with public funds. Advocates are working with researchers and policy makers now to emphasize the need to address issues of access and affordability up front, in order to be prepared to deliver a microbicide rapidly as soon as one is proven safe and effective.
For more information on microbicides, and information on how to get involved to advocate for more research, visit these sites:
The Global Campaign for Microbicides: www.global-campaign.org
The Alliance for Microbicide Development: www.microbicide.org
International Rectal Microbicide Working Group: www.irmwg.org
The Microbicide Trials Network: www.mtnstopshiv.org
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.