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The Challenges of Microbicides, How HIV prevention has defied science
  Posted on Mon, Mar. 23, 2009
By Marie McCullough
Philadelphia Inquirer Staff Writer
Fifteen years ago, the answer to slowing the AIDS epidemic seemed so simple..
Hundreds of chemicals were known to destroy the AIDS virus in a test tube. The idea was to find one that would work in a vaginal lubricant so that no-chafe sex would also be safe sex.
"A microbicide sounded like a no-brainer," recalls Rowena Johnston, vice president of research at AMFAR, the Foundation for AIDS Research. "One or two years, take our bows, move on."
Since then, more than $1 billion has been spent on global research and development of scores of potential microbicides, including lime juice, grain alcohol, and a seaweed extract. Tens of thousands of women have participated in clinical trials.
Yet the field's record is so disappointing that anything short of failure is cause for cheers. Researchers announced last month that for the first time, an experimental gel had shown a hint more protection against HIV than a placebo. The International Partnership for Microbicides hailed PRO2000, tested in Africa and Philadelphia, as "an important milestone" even though the result was not statistically significant - so it could have been a fluke.
Microbicide proponents are undaunted; the new hope is that HIV treatment drugs can be used, either as pills or ointments, to prevent infection. But no one believes it will be simple. In retrospect, experts say, the science behind many studies was weak, the ethical quandaries were underestimated, and a basic rule of product development - find out what the consumer wants - was ignored.
"One of the big issues is whether or not women will use a microbicide when they have one," said John P. Moore, an HIV researcher at Cornell University.
More harm than good
In the early 1990s, with a vaccine nowhere on the horizon, a few activists envisioned an alternative - a goo that could be applied just before sex. It would be cheap and nonprescription, provide contraception, and prevent many sexually transmitted infections, not just HIV. And women would control its use.
This last feature would make microbicides popular in places where men did not like wearing condoms - that is, everywhere. They could liberate American and European women from the fear of infection and save lives in developing countries where women had few rights. In sub-Saharan Africa, for example, 61 percent of the 20 million adults with HIV/AIDS are women. Among ages 15 to 24, it's worse: Females outnumber males, 3-1.
While the need was clear, the gynecology wasn't.
"A lot of work could be done to better understand how HIV transmission occurs and what the defense mechanisms are in the genital tract," said Judy Lieberman, director of the Division of AIDS at Harvard Medical School. "We don't really know what goes on in the portal of entry."
The first compound to reach effectiveness trials was rough on that portal. Nonoxynol-9, an over-the-counter contraceptive that worked by damaging the membranes of sperm, was known to cause vaginal irritation with frequent use.
Nonetheless, N-9 was tested in sex workers in Cameroon, Africa, and Thailand.
By 2000, N-9's abrasive action had been proved to work - in favor of HIV.
The lesson was that chemicals harsh enough to harm sperm or germ membranes might also bother genital tissue. And most first-generation microbicide candidates were compounds that, in one way or another, disrupted membranes.
Of the four that reached final trials, two did not block HIV infection, and two, including N-9, enhanced it.
The field was overdue for a boost when researchers announced last month that PRO2000 had reduced HIV risk 30 percent, just shy of statistical significance. Press releases played down the news that the study, funded by the National Institute of Allergy and Infectious Diseases (NIAID), also produced another failure: BufferGel, a compound that maintains vaginal acidity.
Lisa Maslankowski, the University of Pennsylvania HIV researcher who led the Philadelphia portion of the study, said PRO2000 "is the first time we've seen any signal of effectiveness, so this is very exciting for the field."
But some scientists were baffled because a year ago, the Britain-based Microbicides Development Programme had pulled the plug on a higher dose of PRO2000, saying the trial "was unlikely to show a benefit."
How could a higher potency be less effective than a milder one?
"We really don't know the answer," said Roberta Black, chief of microbicide research at NIAID.
In any case, 15 leading HIV researchers say the field's decade-long investment in membrane-disrupting compounds "was, and remains, difficult to justify." Sketchy science and duplication of efforts led to "an unacceptable waste of resources, both human and financial," they wrote in a July editorial in the journal Science.
Challenges for studies
Beyond the science, microbicide research is full of ethical and real-world dilemmas.
For starters, developers cannot knowingly increase HIV risk while seeking a way to reduce it. Thus, all women testing microbicides are also given condoms and strenuously counseled to persuade their partners to wear them..
In poor countries, women's only leverage may be the nominal payment they receive for their time and trouble in the study.
"Women can sometimes get their partners to use condoms during the trial because they're making money, but after the trial, the condom use stops," said Anna Forbes, deputy director of the Global Campaign for Microbicides, based in Washington. "It's a gray area ethically."
To determine how often condoms and microbicides are used, study workers ask women at monthly checkups. The problem is women tend to say what workers want to hear.
The magnitude of fibbing became clear with Carraguard, a seaweed-based compound. Women used it during fewer than half their sex acts but reported using it 96 percent of the time. Researchers figured this out after analyzing used Carraguard applicators, which were chemically treated to react to vaginal fluid.
Researchers now realize they need to come up with products that are not just good for women, but that women feel good about using. Slow-release vaginal rings and once-a-day formulations are in the works.
In the PRO2000 study, the gel "was messy," a Philadelphia college student recalled. "You would have to use it and have sex right away because if you stood up, it would come right back out. I don't think my boyfriend liked it very much."
In another example of giving women what they don't want, microbicide proponents - mostly from wealthy countries with low birthrates - assumed that women from poor countries with high birthrates would want contraception with HIV protection.
In reality, women usually wanted to get pregnant.
As it turned out, microbicides that were expected to prevent pregnancy, including PRO2000, did not. However, women who got pregnant had to stop using the microbicide because no one knew whether it was safe for a fetus.
Last year, an analysis of "challenges" to microbicide research - commissioned by the Bill and Melinda Gates Foundation - called excluding pregnant women "unnecessary and counterproductive," especially since it could not be enforced in the real world.
Researchers should assess fetal safety using lab and animal tests, said the analysis by the Institute of Medicine, a prestigious public-health advisory organization.
The institute also said researchers must get better at predicting rates of HIV infection, pregnancy, compliance, and quitting in studies - factors that determine how many women must be enrolled to see an effect.
Unfortunately, these variables are moving targets, said Anne-Marie Corner, a pioneer in the microbicide field.
Corner, 47, of Chestnut Hill, a biochemist-turned-biotech-executive, spent 22 years trying to develop a gel called Savvy, only to have two pivotal trials end inconclusively because fewer women than predicted contracted HIV. Thousands more women - and millions more dollars - would have been needed for definitive results.
"Every time you see a patient in the study, you're changing the population as you study it," Corner said. "You're giving them pelvic exams, and condoms, and counseling. You're giving them treatment for sexually treated diseases other than HIV, so their general health is better, so their resistance to HIV is better."
What's ahead
The next generation of potential HIV shields holds more promise - and more risks, experts say.
Trials are under way using HIV treatment drugs such as tenofovir and dapivirine, in pills or ointments, to try to prevent infection in the first place.
The past decade "showed us there's no magic bullet," said Sharon Hillier, a University of Pittsburgh HIV researcher who leads the federal Microbicide Trials Network. "So we looked at the success in preventing mother-to-child HIV transmission" using treatment pills.
In many ways, this is a radical shift. These "antiretroviral" drugs are neither cheap nor nonprescription. They are not even called microbicides when used in pill form; the new term is "pre-exposure prophylaxis," or PREP. Gay men, not just women, are now a focus.
One thing that has not changed is the danger of unintended consequences.
"In poor countries, what are the odds that prevention pills would be taken from a woman and given to a family member with HIV?" asked Forbes, of the Global Campaign for Microbicides.
More worrisome, wider antiretroviral use might make the virus develop resistance, undermining treatment as well as prevention.
"That's absolutely a very high concern," said Black, of the NIAID. "All the trials will be looking at that potential."
Meanwhile, results from an ongoing trial of low-dose PRO2000, funded by the Microbicides Development Programme, are expected late this year. If HIV risk is cut 33 percent - a smidgen more than in the Philadelphia-Africa study - it would be statistically significant.
And that could pose another quandary.
"If we put out a marginally effective product, we know people would reduce their condom use," AMFAR's Johnston said. "Then HIV infection would increase instead of decrease."
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