Mice stave off HIV infection

The mice in J. Victor Garcia-Martinez's lab at UNC-Chapel Hill foretell a major new breakthrough in the fight against AIDS.

Engineered to have human immune systems, healthy rodents have repeatedly been exposed to the virus that causes AIDS, but nearly all have warded off infection. Their immunity comes from a daily, preventive dose of a common anti-retroviral drug.

What that means, if the results bear out in human trials under way, is that a pill a day may keep infection away.

"It looks to be one of the most promising prevention [approaches], but like everything in HIV, nothing is simple," said Dr. Timothy D. Mastro, vice president of health and developmental sciences for Family Health International, a research group that is testing the daily pill in human trials.

Hailed as a potentially momentous development, a prevention pill could also carry significant public health risks. (HIV infects an estimated 2.5million new people a year worldwide.)

Among the biggest fears is that a daily prevention pill, used incorrectly, could fuel a resistant strain of the virus, much like rampant antibiotic use has rendered many front-line weapons powerless against common bacterial infections.

And taken daily like a birth control pill, which guards against pregnancy but does nothing to protect women from sexually transmitted diseases, an HIV pill could also spark epidemics of syphilis, hepatitisC, herpes and other diseases, if people quit using condoms during risky sexual encounters.

That's a likely if.

Only about 40 percent of men and women in the United States use a condom despite shooting drugs or having high-risk sex that increases their chances of contracting HIV, according to the Centers for Disease Control and Prevention.

Yet such perils do not dampen excitement about the prospect of a prevention pill, particularly as vaccines and cures remain distant ambitions, despite billions of dollars spent on research.

"It's a humongous leap forward," said John Paul Womble, an AIDS activist and interim director of the Alliance of AIDS Services - Carolina.

'The approach is terrific'

Much depends on results from the human trials. At least nine trials involving more than 20,000 people are in various stages worldwide. A small U.S. study has been completed, and the results are likely to be reported this year.

Mastro, at Family Health International in Research Triangle Park, said findings from at least three human trials would be needed before world health leaders could determine whether to recommend the preventive pill on a large scale. The key questions they want answered are whether a common drug, used in the novel way, is safe and effective.

Such results could be available within two years, Mastro said.

But tantalizing insights have emerged from the mouse study, reported in January by Garcia's lab at UNC-CH.

Using humanized mice, Garcia's team exposed them to HIV. For all routes of infection - both sexual and intravenous - the daily prevention dose protected the animals from contracting HIV. Even with intravenous exposure, which is the virus's most efficient path into the body, infection was stymied in all but one mouse.

"That is amazing," Garcia said. "You cannot give the virus a better opportunity to infect than intravenous exposure. The fact that the drugs worked - the approach is terrific."

The strategy is not entirely new.

For years, doctors have nearly eliminated HIV transmissions to infants by giving a regimen of anti-retroviral drugs to infected mothers before childbirth, and then to the babies immediately after. Nurses and other health workers have also been given a short round of the drugs to thwart infections after accidentally pricking themselves with HIV-contaminated needles.

But the key to the current approach is offering daily pills to healthy people before any known exposures have occurred - so-called pre-exposure prophylaxis.

Current PreEP trials are testing the drug Truvada, an anti-retroviral therapy in the arsenal doctors use to treat HIV-positive patients.

Among the biggest chal lenges is making sure people take the pills every day. As any woman who uses birth control pills can attest, there are inevitable slip-ups.

What worries researchers is that on-again, off-again use enables the wily HIV to develop resistance to drug therapies. And poor compliance could be a significant issue, especially in the United States, where the high-risk population includes sex workers and intravenous drug abusers.

"It is something that definitely can't be ignored and must be addressed head-on," said Paul W. Denton, a member of Garcia's research team. "Adherence is going to be the key to preventing resistance. But you can have individuals who will not follow instructions. We put seats belts in cars and not every one chooses to wear them."

Still, the risk that HIV could develop resistance is small, other researchers said, and does not outweigh the potential benefits of a prevention pill. Dr. Myron Cohen, an infectious disease specialist who leads UNC-CH's HIV research efforts as director of the Institute for Global Health and Infectious Diseases, said the drug being used as the prevention pill holds up well against the virus's mutations.

"Resistance is something to be monitored and concerned about, it's not a reason to quit," Cohen said.

Keeping condoms

Acknowledging the risks, health leaders are working to craft an approach that would assure the best compliance should a prevention pill roll out.

Mastro said Family Health International is involved in some of those efforts.

"If and when we prove that pre-exposure is safe and effective, we will have a real challenge to make sure the prevention message is communicated," Mastro said.

One approach is to stress the continuing need to use condoms in addition to taking the pill. That's a tough sell.

In the gay community, where the message to use a condom has been a drumbeat for the more than 25 years that HIV has been identified, the temptation to pop a pill and forgo other protective measures could overwhelm better judgment.

"'Condoms are important for everybody but me' - that's the mind-set, and it landed me where I am today," said Womble, who is HIV positive and now works as a community activist with the AIDS alliance.

Womble said instead of using condoms, many gay men now choose to segregate themselves into HIV positive or negative groups, essentially limiting their sexual encounters to people who share their HIV status.

And that has its own pitfalls - among them a resurgence of other sexually transmitted diseases.

In recent years, North Carolina has seen a spike in syphilis cases, particularly among black men who have sex with other men.

Public health leaders fear an HIV prevention pill could exacerbate that trend.

"It's good news, certainly, and if the human trials look good, it's an immense cause to celebrate," said Jacquelyn Clymore, head of the state's HIV/STD prevention branch. "But HIV is just one of the things that you can transmit and catch. A pill is not going to change the fact that everyone still needs to know their HIV and STD status, and we have to make careful and responsible decisions about who we're doing what with in order to protect our health."

Building a triumph

Despite the inherent hazards, Clymore and others said a prevention pill could usher in an entirely new era in the fight against HIV - and that would be a welcome victory.

Since HIV was identified in the 1980s, the United States and other countries have poured billions of dollars into vaccine research, potential cures and prevention efforts. Although there have been major successes - notably the development of AZT and other anti-retrovirals that have kept millions alive, though not disease free - there have beenmany disappointments.

Finding a vaccine, especially, has been frustrating. Scientists five years ago regrouped after yet another vaccine candidate failed, forming an international consortium centered at Duke University to share research in the hopes of speeding discoveries.

Those efforts are no less important, even if the prevention pill proves safe and effective, said Cohen, the UNC-CH researcher, who is also one of the leaders of the vaccine consortium.

"Every case where we prevent infection is critical," he said. "But to have the entire species take a pre-exposure prophylactic is unreasonable. We haven't worked out the details of this intervention - who will be given the pill and to what benefit. And you still have all the other STDs, unwanted pregnancies and other things."

Costs are also a factor. A regimen of Truvada runs upward from $850 a month when used as an HIV treatment, and it's unclear whether the costs would come down for a daily prevention pill. Cohen said additional studies may prove that daily use isn't necessary, or that a topical gel could serve as an option.

Yet in the absence of a vaccine or cure, a prevention pill is progress - if also an additional challenge.

"The fact of the matter is, anything that will help reduce the spread of any STD is to be commended and embraced without exception," said Tom Intiso, an AIDS activist with the alliance. "The problem is ... we have failed across the board, as public health professionals, to do a good enough job in the community to prevent HIV and STDs."