What’s flowing through the microbicide pipeline

Approaches range from complex to simple

The microbicide research field is varied and diverse, with the potential for products that will include vaginal and/or rectal gels, films, creams, or suppositories to oral medications, which have active ingredients that range from hormones to antiretroviral drugs, fusion inhibitors, or surfactants.

Products also vary in what they do: Some are designed solely to prevent HIV infection, while others also will work as spermicides or prevent infections by other sexually transmitted diseases (STDs).

What eventually will be developed and marketed will depend largely on the availability of funding and the industry’s and international AIDS community’s interests, experts say.

However, a few products have a head start in the race for a successful microbicide, including several currently scheduled for phase III clinical trials.

The first generation products are based on negatively charged polyanions, says Robin Shattock, PhD, reader in cell biology of infection, department of cellular and molecular medicine, infectious diseases at St. George’s Hospital Medical School in London. "We understand a great deal about their safety, and they all clearly inhibit HIV infection in the test tube," she says. "They are cheap, easy to manufacture products that are unlikely to suffer from problems of resistance."

These first products are nonspecific in their activity, ready for phase III clinical trials, and may have a chance of showing some efficacy, Shattock adds.

Next in the pipeline are a wide range of products that may prove to be more effective microbicides, but which are a few years away from phase III clinical trials, he adds.

"Of particular promise would be the topical use of antiretroviral agents that already have a proven track record against HIV replication," Shattock says. "These products are highly likely to succeed in preventing infection, but their use may be complicated by potential resistance acquisition in the developing world."

These products are followed by a range of fusion inhibitors and coreceptor antagonists. While these products hold promise, they also have potential problems with regard to mass production at an affordable cost, he says.

"Ultimately, the best microbicide is likely to consist of a combination of active agents that can keep abreast of resistance patterns and block all potential pathways of infection," Shattock explains. "It is likely that we will see partially effective microbicides that are then supplemented with additional agents to increase efficacy."

Even if the first microbicides only are partially effective, they could have an enormous impact on the sub-Saharan African pandemic.

"Modeling by Charlotte Watts and others at the London School of Hygiene suggest that a product that is only 50% effective and is used by 20% of those people reachable by existing services could prevent 2.5 million infections within a three-year period," Shattock notes. "The same group has shown that introduction of such a preventative strategy would only have a negative impact on current prevention strategies if condom use were greater than 70%." Condom use is estimated to be only 7% among women with their stable or permanent partners, he adds.

For a nutshell look at some of the microbicide approaches and products under study, Shattock and other investigators offer these descriptions:

Topical estrogen.

While most microbicide products are years away from making it to the market, there is one potential prevention product that already is sold in western Europe and could be put through clinical trials in a few years if the research funding were available.

Vaginal estriol (Ovestin) is sold as a topical estrogen therapy to treat vaginitis in post-menopausal women, says Stephen M. Smith, PhD, chief of infectious diseases at St. Michael’s Medical Center in Newark, NJ, medical director of Peter Ho Memorial Clinic in Newark, and program director of infectious diseases fellowship through Seton Hall in Newark.

The product, which is a weaker-acting estrogen and so does not have systemic side effects, is a cream that can be applied several times a week. It causes the vaginal epithelia to thicken significantly, which is expected to help prevent HIV infection, especially in women who have thinner epithelia. This includes those who are post-menopausal and those who use certain progesterone contraceptive agents such as depomedroxyprogesterone acetate (DMPA), Smith explains.

A recent study showed that vaginal estriol in macaques, applied twice weekly, helped to protect 11 out of 12 macaques from becoming infected with SIV after a single challenge. This contrasted with six of eight control animals becoming infected.1

Advantages and drawbacks

The advantages to this prevention approach is that the product already is manufactured and marketed and it is inexpensive, he says.

It has no impact on fertility and would be a good treatment for women who use DMPA, which is popular in developing nations, Smith adds. The drawbacks are conventional wisdom and the costs of a clinical trial, he notes.

"I presented data on earlier stuff, and someone said, You’ve stopped HIV transmission in nursing home patients,’" he recalls. "This product lacks the sex appeal of a new scientific compound."

However, if the product proved to be as efficacious when women use it as it was with the monkeys, it would be a cheap, easy-to-use way to reduce risk of HIV transmission, and it’s a product that could be entirely controlled by women, which is one of the major goals for any prevention product.

Also, it’s an approach that could be combined with a microbicide and further improve protection, Smith says.

Cellulose acetate phthalate.

Researchers with the Centers for Disease Control and Prevention (CDC) of Atlanta have been studying cellulose acetate phthalate (CAP) as a microbicide.

CAP has been shown to very effective in blocking cells tissue transplants, and it’s been shown to block herpes infection as well as HIV, says Ron A. Otten, PhD, a CDC research microbiologist.

Since CAP has been approved by the Food and Drug Administration (FDA) for safety and is used routinely in aspirin tablets to promote absorption in the intestine and to buffer the effects of medication, it shouldn’t elicit any immune response, Otten says.

"It disrupts membrane cell interactions and causes the membrane of HIV to fuse together on itself, and it disrupts the cell entry that HIV uses," Otten says.

The CDC’s research into the use of CAP has resulted in researchers developing an animal model for this type of microbicide research that is more physiological than what typically is used, says Tom M. Folks, PhD, chief of the HIV and Retrovirology Branch at the CDC.

Instead of applying the product to monkeys and then using a high dose challenge to study SHIV infection rates, investigators gave the animal subjects repeated low-dose challenges, Folks explains.

"We’ve looked at it in 12 exposures, and there still are protected animals, whereas unprotected animals were infected after three exposures," Folks says.

The idea is that the repeated, lower doses more closely mimics what actually occurs when an uninfected woman has vaginal intercourse with an HIV-infected man.2

"We theorize that many good microbicides are being developed, but they’re not chosen because they are being challenged in larger exposures," Folks says. "They show that they’re either toxic or are partially efficacious, but not completely."

The theory is that humans likely are repeatedly exposed to HIV before they are infected, and the amount of virus used to infect humans is fairly low, so it wasn’t logical to conduct animal studies in which the exposure dose of virus is very high, Folks explains.

"We can conserve animals and have a lower dose exposure so all animal controls eventually become infected," Folks adds.

Pre- and post-trichomonas therapy.

A less-traditional approach to an HIV microbicide is to lower risk to HIV through treatment for other infections, including treatment of malaria and the human papillomovirus (HPV).

"The premise we’re working on started out of the epidemiology research in the late 1980s and early 1990s," says Bruce K. Patterson, MD, an associate professor of pathology and infectious disease at Stanford (CA) University School of Medicine.

"If you want to use the microbicide word, it has to encompass everything from antiretrovirals we take by mouth to what we can do to change the environment in the genital tract," he says.

"If you could potentially treat other infections, especially in the genital tract, how would that impact transmission?" Patterson says.

Simply putting people on antibiotics doesn’t work in lowering risk to HIV because not all infections are bacterial, he notes.

"If you adequately treat infections other than HIV, you will change susceptibility of your body to HIV or lower the ability of HIV to replicate in your body," Patterson says.

Reducing HIV susceptibility

In a recent study, Patterson and co-investigators found that effective and inexpensive metronidazole treatment of the STD trichomonas reduces susceptibility to HIV by 10% to 80%.3

"My lab is focused on the theory that if you are able to treat or get rid of these other infections that cause inflammation, then you should, per se, decrease your susceptibility to HIV," he says. "When we treated trichomonas adequately with a very inexpensive antibiotic, we could change the milieu of the female genital tract in a way that lowered the susceptibility to HIV transmission."

One of the more important outcomes of the research was that it used a model that Patterson had developed a year earlier. The model was for growing whole pieces of human tissue in the lab from HIV-negative individuals and then treating the tissue and trying to infect it with HIV, he explains. "Because we were able to do that at Stanford, we can screen a number of different approaches to fighting off HIV in a real human system," Patterson adds.

Patterson’s HIV research also shows that the male foreskin in uncircumcised men is more susceptible to HIV infection because it’s a true mucosal surface that has cells the virus can more easily target and infect than the circumcised penis in which the mucosal surface is removed.

This suggests that it will be important to have a microbicide in sub-Saharan Africa, where many men are uncircumcised, and elsewhere that could be applied to both women’s vaginas and men’s foreskins, Patterson says.

Bioengineered lactobacilli.

Lactobacilli, which are normal inhabitants of the human gastrointestinal or urinal tracts, are being studied for use in preventing HIV-1 infection.

Investigators have found a way to engineer lactobacilli to secrete HIV-1 microbicides, which could lead to at treatment that would block HIV-1 infection in the vaginal or rectal mucosa.4

Specifically, researchers bioengineered lactobacilli to secrete HIV-1 microbicidal proteins such as the prototypic virucidal compound cyanovirin (CV-N).4

"Our findings so far are that in-vitro secreted CV-N from lactobacilli inhibits HIV infection in a cell culture system, says Oliver Pusch, PhD, assistant professor in the department for infectious diseases at Brown University Medical School in Providence, RI. "Our approach is to be as close to the nature of the system as possible," he explains. "If our system works, the beauty would be it is very close to physiologically normal inhabitants."

This means it is unlikely the microbicide would cause harm to the vaginal floor or cause an autoimmune reaction, and it would be safe and easy to apply, Pusch says. Also, since 95% of the HIV epidemic has occurred in the developing world, this would be a good option for poor nations, as it would be a cheap microbicide that is easy to produce, he says.

Blocking attachment and fusion receptors.

"The main findings of this study are that the principal coreceptors required for mucosal transmission (CCR5 and CXCR4) have been defined," Shattock says. "Furthermore, blockade of these receptors by chemokine antagonists is sufficient to inhibit localized mucosal infection."

The study has identified key targets for intervention strategies to prevent HIV-1 sexual transmission.5 "This study defines the relevant targets that need to be considered in microbicide development," he says. "Furthermore, it suggests that blockade of HIV coreceptors may be a highly effective strategy in preventing HIV infection if combined with inhibitors against dendritic cell binding and uptake of virus."

The take-home message from this research is that blockade of both localized infection and dissemination pathways will be essential to preventing HIV infection, Shattock adds.

References

1. Smith SM, Mefford M, Klase Z, et al. Topical estrogen protects against SIV vaginal transmission without evidence of systemic effect. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract 886.

2. Otten RA, Adams DR, Kim CN, et al. Cellulose acetate phthalate protects macaques from multiple, low-dose vaginal exposures with SHIV virus: new strategy to study HIV pre-clinical interventions in non-human primates. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract 159.

3. Patterson BK, Spear G, Landay A, et al. Effects of pre- and post-trichomonas therapy CVL supernatants applied to cervical explant tissues on the susceptibility to HIV-1 infection. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract 885.

4. Pusch O, Boden D, Hanniffy S, et al. Mucosal delivery of HIV-1 microbicides using bioengineered lactobacilli. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract 883.

5. Hu Q, Watts P, Frank I, et al. Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract 157.