Clinical Research Update

The research pipeline is filled with hopeful microbicide candidates.

Family Health Research: 2008, Vol. 2, Issue 2

Key Points An effective vaginal microbicide has not yet been identified. Three products are being studied in large-scale effectiveness trials.  The newest candidates are designed to stop HIV from replicating.

Research to develop an effective vaginal microbicide began nearly three decades ago. Today, more than 60 different products are in some stage of laboratory or clinical development. Eleven of these products are in human clinical trials, and three are in large-scale effectiveness trials. However, no candidate microbicide has yet been shown to prevent HIV or other sexually transmitted infections (STIs) in humans.

"The process of product development is long, but the HIV-prevention community is hopeful that an effective topical agent will be identified within the next decade," says Dr. Willard Cates, president of research at FHI.

Types of products

The "first generation" of microbicide candidates are typically formulated as gels, which are applied to the vagina before each act of sexual intercourse. These candidates employ one of three mechanisms that should theoretically prevent HIV and other STI pathogens from infecting cells. Some are surfactants (agents that reduce the surface tension of a liquid) that inactivate a bacterium or virus by damaging its surface membrane. Others enhance the vagina's natural defenses against pathogens, for example by maintaining the natural acidity of the vagina in the presence of semen, which is alkaline. Still others block viruses from attaching to healthy cells.

The next generation of microbicide candidates is based on antiretroviral drugs. These products specifically target HIV, acting later in the viral life cycle to prevent HIV from replicating once it has entered the body. Although some are formulated as gels, others may be released through vaginal rings. And, unlike the first-generation candidates, some of the newer products may be delivered on a daily or monthly basis (such as through a vaginal ring) regardless of the timing of intercourse.

Eventually, a combination of different products with more than one mechanism of action may be the most effective way to prevent a wide range of STIs. Products with a contraceptive ability will also be important for meeting diverse reproductive health needs.

Research process

After a microbicide candidate is identified, its safety and effectiveness is first assessed in test tubes and animal models. If the product passes this stage of testing, it enters human clinical trials.

In Phase I microbicide trials, scientists assess the safety of the product, determine its acceptability among potential users, and identify its appropriate dose and formulation. In Phase II trials, scientists again assess safety and acceptability, but among more participants and for a longer period.

The final stages of microbicide trials (Phase IIb and Phase III trials) are used to evaluate a product's effectiveness in preventing HIV and other STIs. Phase IIb trials are typically smaller than Phase III trials, giving some indication of effectiveness and helping scientists decide whether a larger Phase III trial is necessary. Lasting up to four years, Phase III trials enroll thousands of participants who are at risk of HIV, such as those living in communities with a relatively high incidence of HIV.

Although all participants in microbicide trials are regularly counseled on how to reduce their risks of acquiring HIV and other STIs, prior experience has shown that even with optimal counseling and free access to condoms, most women are not able to negotiate condom use every time they have sex. The effectiveness of a candidate microbicide is tested in those sex acts in which women are not able to use condoms.

Ruling out candidates

Three first-generation products — SAVVY, cellulose sulfate, and Carraguard — were ruled out as effective microbicides in advanced clinical trials.

In 2005, FHI closed its Phase III trial of SAVVY (a surfactant) in Ghana when an independent data monitoring committee determined that the incidence of HIV was so low that the study would not be able to determine whether SAVVY could prevent HIV. FHI closed its parallel Phase III trial of SAVVY in Nigeria in 2006, after a similar committee concluded that the trial was unlikely to find a protective effect if it continued. Earlier studies had shown that spermicides containing another surfactant, nonoxynol-9, may actually increase the risk of HIV infection when women at high risk of infection use them frequently.

In 2007, CONRAD closed its Phase III trial of cellulose sulfate (an inhibitor of viral attachment and entry) in South Africa, Benin, Uganda, and India after a planned interim analysis suggested that the product might contribute to an increased risk of HIV. Because of these safety concerns, FHI simultaneously closed its Phase III trial of cellulose sulfate in Nigeria. However, the final data from both trials showed that cellulose sulfate had not significantly affected the risk of HIV infection either positively or negatively.

Most recently, the Population Council completed a Phase III trial of Carraguard (another inhibitor of viral attachment and entry) in South Africa. Results, released in 2008, showed that the Carraguard gel was safe and acceptable. However, it did not reduce the risk of acquiring HIV. Although these results were disappointing, the Carraguard trial was the first effectiveness trial to be completed as planned for a product that was developed specifically as a microbicide — an historic accomplishment in the eyes of many microbicide advocates.

More effectiveness trials

Three microbicide candidates — BufferGel, PRO 2000, and tenofovir — are currently in large-scale effectiveness trials. Three additional products — ACIDFORM, the invisible condom, and dapivirine — will enter the advanced stages of clinical trials soon (see table).

"As with all other HIV-prevention approaches, no vaginal product is expected to offer 100 percent protection against HIV or other STIs," says Dr. Cates. "At best, an effective product would prevent infection perhaps half the time. But even a partially effective microbicide could help women who might otherwise not be able to protect themselves at all."

Microbicide Effectiveness Trials
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