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Microbicide Research Will Prevail Despite Most Recent Setback, Experts Say
Next generation contains ART microbicides
Microbicide research suffered a setback earlier this year when a phase III clinical trial studying cellulose sulfate to block HIV infection was stopped prematurely because there appeared to be a higher rate of HIV infections among the study group than the control group.
Researchers and other experts in the microbicide field say that this was a minor bump on the road to achieving a safe and effective microbicide that women across the world will use to better protect themselves against HIV infection.
While the much earlier trials studying the spermicide/microbicide Nonoxynol-9 also ended with disappointing results, scientists now believe that product's detergent-like, abrasive qualities resulted in higher HIV rates than the control group. Cellulose sulfate does not have this quality, and there is no logical reason why it would have resulted in higher HIV rates.
In fact, researchers say that when the trial's data analysis is released later this year, it may show that the product did not result in higher HIV rates, but merely was not effective at blocking HIV infection.
"Most of us in the field were surprised about [cellulose sulfate] being stopped," says Mary Klotman, MD, chief of the division of infectious diseases and professor of medicine and microbiology at Mt. Sinai School of Medicine in New York, NY.
"The pre-clinical work with safety looked very promising," Klotman says.
"The final analysis has not been available, but it was stopped because of safety concerns," she adds. "It may be when they analyze all of the data that [the difference in HIV infection rates] wasn't significant."
While the final finding might be that cellulose sulfate didn't cause harm, it's also obvious that it didn't work, and the sponsors were correct to stop the study, says Zeda F. Rosenberg, ScD, chief executive officer of the International Partnership for Microbicides in Silver Spring, MD.
Microbicide research's evolution has followed a trajectory that's similar to other research areas, Rosenberg notes.
"There often are many failures before you find something that works," Rosenberg says. "Where we are in the microbicide field is we don't have that first success yet, and you need that first success."
Typically, a new type of treatment will gain momentum as lab work and animal experiments data show promise, and then there is information from small numbers of people in clinical trials, she explains.
The difficulty lies in the next jump to large-scale trials.
"Even in the case of therapeutics it's very difficult to know that the drug you're going to test in large numbers of people isn't going to show some rare event that will make it not useful on the market," Rosenberg says. "In prevention studies it's even harder because you're starting with all healthy people, and not everyone will get the disease you're looking for, and so you have to test it in large numbers of people."
Prevention products have to be tested in large numbers of people before a product's efficacy can be proved, she adds.
Until one of the microbicide trials, either ongoing and preparing to start, succeeds, people will be pessimistic, Rosenberg says.
"But as soon as we have that first success there will be many, many more following up on it in rapid succession," she adds.
Among the ongoing microbicide trials, results are expected for the Carraguard study, sponsored by the Population Council, by the end of this year. Another product called PRO 2000 is one to two years away from having results, and the compound BufferGel also has trials underway.
In the lab, PRO 2000 stops HIV, Klotman says. She is a co-investigator of a study that looks at the epitope mapping of PRO 2000 against HIV gp120.1
"Most of its activity is at the point of viral entry into the cell, probably because it is interacting with gp120, which is a major envelope protein that mediates entry into the cell," Klotman explains.
Klotman is not involved with the drug's clinical trials.
"We were funded to study some of the compound's characteristics in the laboratory," Klotman says.
Microbicide researchers also are continuing to work at learning more about the mechanism of the first generation microbicides, including PRO 2000, Klotman notes.
Since cellulose sulfate failed, this information will be especially important, she adds.
Even as these first microbicide trials lay the groundwork, there are some very different compounds being tested, as well. These include antiretroviral drugs that were not available when microbicide research began.
"Sulfanated polyanions are the first class of topical microbicides to progress in clinical trials, and they're negatively-charged polymers -- not specific antiretrovirals," Klotman says.
"The first generation of products were designed in the early 1990s before we knew as much as we know now about how to treat HIV infection," Klotman says. "The first products were non-specific blockers, large molecules meant to interfere with HIV to keep it from attaching to target cells in a non-specific manner."
The new generation of microbicides include antiretroviral drugs, including reverse transcriptase inhibiting compounds.
"We're looking at the antiretroviral (ART) dapivirine, which works early in the virus life cycle and has a pretty long half life," Rosenberg says.
"The first generation of microbicides had to be used every time a woman had sex, so the notion is to find drugs that can stick around longer so they can be used daily and, depending on the delivery, can be used much less frequently," Rosenberg says.
Investigators with the International Partnership for Microbicides (IPM), the Population Council, and other sponsors are studying the delivery method of intra-vaginal rings as a potential solution to the inconvenience of microbicides.
Intra-vaginal rings have been used for preventing conception and for delivering post-menopausal hormone replacement treatment, where they can be left inside a woman for three weeks in the former case and three months in the latter, Rosenberg says.
"We thought it'd be great if there was something women could leave in their bodies for some length of time," she adds. "It'd be easier to remember."
In a safety and acceptability study of a placebo vaginal ring, 200 women will be enrolled at four sites in sub-Saharan Africa, Rosenberg says.
The African studies are to see if African women like the intra-vaginal rings, as well as to see if they are safe and acceptable to them, Rosenberg notes.
"The rings are only marketed in the United States and Europe, so there is no modern experience of vaginal rings in different populations," she says.
Also, IPM is studying the rings with dapivirine in a safety and pharmacokinetic study involving 24 women in Belgium.
"We're now starting a study in Belgium where women are using the ring for a minimum of a month, and then they'll put in a new ring every month for three months," Rosenberg says.
The safety trials using intra-vaginal rings and dapivirine found that the delivery system was generally safe and well-tolerated and delivered the drug throughout the genital tract.2
One drawback to using ARTs as microbicides is that it's possible people using these products could develop drug-resistant virus if they were to become HIV infected, says Sally Blower, PhD, a professor at the David Geffen School of Medicine, University of California - Los Angeles.
The earliest group of microbicides could not result in drug resistance, Blower says.
"So people have concerns when giving people low levels of ARTs that they might pick up HIV, continue to use the microbicide, and then they might be susceptible to drug resistance," Blower says.
Despite this risk, microbicide research should move into the direction of ARTs because nothing has worked so far, Blower says.
"I think with microbicides, it does seem like a very good approach," Blower says. "It makes sense because ARTs do work against the virus."
Microbicide researchers are dedicated to finding a product that works because they're well aware of how urgently women around the world need a prevention measure within their own power.
While condoms work well, and the recent good news about circumcision preventing HIV is one of the most promising prevention news to date, women also need empowerment if the epidemic is to be eradicated, Blower says.
"Women need to have control and to use measures that aren't going to be so intrusive because men do object to condom use," she says. "So microbicides are very promising."
This is a critical public health issue that has a huge impact on societies, and failure in the microbicide field is not an option, Rosenberg says.
"There will be a way to address this problem, but it requires a lot of effort and having a lot of different drugs in the pipeline," Rosenberg says. "The more we have in the pipeline, the more likely we'll find one that works well."
IPM has received royalty-free licenses for six different ARTs and there are different mechanisms of action, so investigators have the broadest base possible from which to obtain results, she adds.
"We definitely need male circumcision implemented as broadly as possible for men where it can be done safely, and we need a vaccine, and we need a microbicide and more treatment for HIV infection," Rosenberg says. "We need it all -- this is such a dangerous disease that we need everything we can to fight it."