Hope for Vaccine Rises,
So Do Fears of More Infections

By ROSIE MESTEL, Times Medical Writer



Research Scientists envision a drug that can slow HIV. In U.S., rates hold steady, but some brace for reversal. Poor nations still far behind.

As they look into the next few decades, those who battle the HIV epidemic in labs and clinics see a future at once promising and grim. They see years of steady progress ahead--and years tackling daunting challenges.

They predict that many more medicines will be available, ones with fewer side effects than the drugs used today. People who can get treatment will probably live longer, healthier lives--perhaps normal or close-to-normal life spans.

The hope for a vaccine, meanwhile--so recently pie-in-the-sky thinking--is again soaring. Few expect a vaccine any time soon that stops people from ever getting infected. But many have high hopes for a vaccine that makes people less sick, or barely sick, when they get infected.

HIV experts do not expect a cure in the foreseeable future, though--not if a cure means ridding the virus from the body. Most people who are infected will probably need treatment of some kind until the day they die.

And while rates of new infections have fallen and are now holding steady in this country, they are holding steady at 40,000 new cases a year--hardly cause for celebration. Annually, 17,000 people still die of AIDS. The epidemic's demographics have been shifting too--and will probably continue to shift--toward younger people, African Americans, Latinos and women.

Even in gay communities, where AIDS first took hold, and where so much was done to keep people safe through behavior change, there are signs that people are moving back toward old ways--as witnessed by increases in some cities of rates of syphilis and gonorrhea.

"This is a very worrying trend," says Dr. Helene Gayle, director of the National Center for HIV, STD and TB Prevention at the federal Centers for Disease Control and Prevention in Atlanta. "If other STDS are going up, then the potential for HIV to follow close behind is there."

Indeed, new numbers released last week from a study of six cities, including Los Angeles, suggest that HIV infection rates in young gay men are already climbing.
   But bad as the epidemic remains in the U.S., the magnitude of tragedy in other parts of the world--notably sub-Saharan Africa--is simply staggering, with ripple effects that stand to reverberate far into the future. Many of these impoverished countries lack money for even basic health care--much less the labs, clinics and trained workers to administer it. Even the most dazzling biomedical breakthrough will mean nothing to the HIV-infected people there unless some way is found to get drugs and appropriate vaccines to them.

"This epidemic is far from being over. I think we're actually in the early stages--that the worst is still yet to come in terms of people dying, in terms of the orphans they leave behind," says Dr. Peter Piot, executive director of the Joint United Nations Programme on HIV-AIDS, an agency that advocates for worldwide action against HIV.

Piot's hope, in the face of this devastation, is that a vaccine will arrive and that promising trends seen in countries such as Uganda, where infection rates are down due to education and prevention, will spread to other nations. He hopes the U.S. can somehow start getting treatment to at least parts of some developing nations using a global fund financed by contributions from richer countries.

His fear is that there will be no vaccine--or that there will be vaccines active only against strains of the virus causing disease in wealthier parts of the world. That continents where the virus is next poised to devastate--eastern Europe and Asia--will fail to act in time.

The U.S. must do its utmost to help the better story unfold--for humanitarian reasons but also for its own security, says Dr. Alexandra Levine, a professor of medicine at USC and a member of an advisory council on HIV-AIDS set up during President Clinton's administration. AIDS is bringing some developing countries to the brink of collapse; it will leave an estimated 44 million orphans in its wake by 2010.

"I envision real social chaos affecting not just sub-Saharan Africa and the poor areas of the world," says Levine. "That sort of social chaos will affect all of the world."

Discovering Limits of the AIDS Drugs

In the years after the discovery of the human immunodeficiency virus, or HIV, scientists learned much about how it wreaks its havoc--how it infects and kills key immune cells called T helper cells; how the body, unable to properly protect itself, progresses to acquired immune deficiency syndrome, or AIDS, and is racked by repeated infections or cancer.

Then came the drugs--and a hopeful time, six years back, when some scientists thought that potent new cocktails of antiviral medicines might hit the virus so hard they would clear it from every last tissue in the body.

"A lot of people were talking eradication at the time," says Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. "I was always very skeptical, given the biology of the virus."

Undoubtedly, the medicines have made a huge difference to the lives of people who can get them. Where once those infected died quickly and awfully, many have now been holding steady for years.

But as time went by, Fauci says, it became clear that a cure was not happening and wasn't going to.

There are "sanctuary sites" in the body: places where drugs don't reach. There are cells where no virus is found, and yet neatly stitched into those cells' DNA lurk HIV blueprints that can start cranking out virus far in the future.

"That means you're not going to get people off antiviral drugs in the same manner that when you cure cancer you can stop the cancer chemotherapy," Fauci says. "It means that people need to be on drugs until further notice--essentially indefinitely."

Yet it also has become clear that today's drugs will not last indefinitely.

Drug-resistant strains of virus--sometimes resistant to several drugs--are evolving. Such resistance emerges quickly if patients don't stick to strict drug regimens, and these are strict indeed, with a dozen or more pills to be taken at precise times and combinations many times daily. Easier-to-manage drugs will be crucial for the future, experts say.

The drugs also can have side effects when taken long-term: strange changes in body fat that thin the face and broaden the waist and cause humps to develop on the back of people's necks. Changes, too, in lipid and sugar metabolism as well as a toxic acidity of the blood and a thinning of the bones.

Are heart disease, diabetes and osteoporosis a part of the epidemic's future? Already, there are anecdotal reports of young, HIV-positive men who have had heart attacks. Already, says Dr. Fred Sattler, a professor of medicine at USC, much of HIV management has shifted from dealing with acute infections and end-of-life issues to managing people long-term for chronic diseases and counseling them to watch their diet and exercise.

And some people are running out of potent drugs to take or can no longer tolerate the side effects.

"Those are very difficult situations," says Dr. Ronald Mitsuyasu, director of the UCLA Center for Clinical AIDS Research and Education. "We're faced with either stopping their medications and allowing the virus to just run rampant or continue them on sub-optimal medications that suppress the virus only to some degree."

So far, Mitsuyasu says, he hasn't seen an upswing in deaths as a result of such failures. Doctors are crossing their fingers that new drugs, some of them now awaiting FDA approval or in clinical trials, will enter the HIV medicine chest before that happens.

A Need to Take Different Approaches

There are plenty of drug avenues left to explore. The three classes of antiviral drugs used today target only two HIV proteins--the "reverse transcriptase" that the virus needs to copy itself before jumping into the genomes of cells and "protease inhibitors" that stop key virus proteins being snipped into the right sizes. Yet HIV can be tackled at other places in its life cycle.

Attaching to the cell. Entering it. Insinuating its genes into the DNA of cells it infects. Revving up its genes to reproduce itself faster, kill T cells and make it harder for the immune system to sense its presence and destroy it. HIV has genes that just weren't known before scientists started studying this virus, says Dr. Irvin Chen, director of the UCLA AIDS Institute. "They've been very, very heavily researched in the academic community," he says. Part of the future of HIV may depend on how thoroughly and rapidly drug companies exploit all avenues.

Some of the avenues researchers are excited about are aimed less at attacking the virus directly and more at coaxing people's own immune systems to do the job themselves. It is a new approach--and it stems from a finding that came to light as the epidemic dragged on.

Just as there was a time when HIV experts thought today's antiretroviral drugs might cure people, there was also a time when they thought the immune system was incapable of mounting a good defense against the virus--and that pretty much anyone infected with HIV would eventually progress to AIDS.
    Yet--to the astonishment of clinicians--some people didn't.

"We don't know how long this is going to continue, but some people have been infected for over 20 years and are entirely healthy with exceedingly low levels of virus in their blood stream and very strong immune systems that appear to be keeping it in check," says Dr. Bruce Walker, director of the division of AIDS at Harvard Medical School.

If this lucky 1% can keep the virus in line without any medication, might it be possible to coax the systems of the other 99% to do likewise?

Already, there are encouraging signs. Walker's group, for instance, has managed to boost immunity in groups of people who are still experiencing the acute, flu-like symptoms of an early HIV infection.
    The key: bashing the virus with antiviral drugs early on--at a time when much of the body's HIV-fighting ability is normally destroyed. Then the patients come off drugs for a few weeks, and their protected immune systems can now attack the virus. Some patients, Walker's group has found, need only one spell off the drugs to gain control; others have needed several.

Today, some of these people (and only a handful have been thus treated so far) are keeping the virus at low levels, without drugs, as much as 500 days into their infection. No one, cautions Walker, knows how long this will last.

In any case, it is rare to catch patients so early in the infection. Thus scientists are working on immune-boosting strategies for all the others.
They're experimenting with various chemicals, including ones that might repair parts of the immune system destroyed by HIV. This was once deemed impossible.

They're exploring the more ancient parts of our immunity (shared with creatures as evolutionarily distant as earthworms) and immunity in tissues the virus first encounters, such as the female genital tract.

And they are working hard to come up with "therapeutic" vaccines: ones that give the immune systems of infected people a novel taste of the virus so their bodies can learn to keep the virus in check.

"It has to be a multi-pronged approach," says Alan Landay of Rush-Presbyterian-St. Luke's Hospital in Chicago, and vice chairman of an NIH-funded immunology committee evaluating immune-boosting therapies for HIV. "If we sit there with our blinders on and think we're going to get an answer in one area, we're going to be really disappointed. We can't afford to do that."

More Information, Encouraging Trials

Yet to many, a preventive vaccine is the holy grail of HIV research--one that could be given to people to protect them should they later get infected. And, after years of discouragement, the vaccine field is galvanized once more.

Many doubt that such a vaccine will stop the virus from entering our bodies. ("It would be doing a disservice to have people believe that--most vaccines do not do that," says Kathie Grovit-Ferbas, assistant professor of medicine at UCLA, who has been working on an HIV vaccine.) But they have high hopes that a vaccine could render infections well-controlled. Many vaccines--such as flu vaccines--do that.

One reason for the optimism is that scientists today have a much better idea of the kinds of immune responses that would be needed to fight off HIV. Both antibodies and cells called killer T cells seem to be needed.

Another reason is the sheer number of hands and minds now involved in the effort--ranging from academia to government agencies to major pharmaceutical companies.

Yet another reason is recent, encouraging animal trials of vaccines against a very similar virus: SIV, which infects and causes an AIDS-like disease in rhesus monkeys. For instance, in a recent trial conducted by Harvard and the drug company Merck, vaccines consisting of pieces of virus DNA plus a chemical to boost the immune system didn't stop monkeys from getting infected. But the animals developed strong immune responses against the virus and didn't develop monkey AIDS during the 140 days of the experiment. Unvaccinated monkeys got sick.

In the meantime, the first Phase 3 clinical trials of a vaccine are underway in North America and Thailand in thousands of injection-drug users (Thailand) and gay men (North America). Consisting of a synthetic viral protein called gp120, it was developed when scientists knew less about the immune responses needed to fight HIV and activates only the antibody arm of our immune system. Many have their doubts: The answer, either way, should be in within 18 months.

And even if that trial is a bust, other candidates are in the pipeline--some using vaccines based on harmless viruses or bacteria containing a few HIV genes. Others use fragments of the virus' DNA or shards of the virus protein. Some scientists are even working on a vaccine that uses HIV that has been killed.

The effort may take decades, experts agree; there will invariably be disappointments along the way--but how fast it happens will depend on how well the many groups now involved coordinate their efforts and explore all avenues, how well they figure out now what kind of incentives they can offer drug companies to develop vaccines for poor countries, how the vaccines will be paid for, distributed--and many issues besides.

These challenges have to be overcome, they say, if the virus is ever to be vanquished.

"I've come to believe that no matter what we say as far as changing behavior, it is extremely difficult for the human race, as a whole, to change behaviors--it doesn't come easy," says Levine. "At the beginning, I thought that all you had to do was to educate people and the 'right thing' would occur and we could prevent new infections that way.

"As time has passed, I've come to understand that education is an important first step. But, ultimately, I think only a vaccine is going to be able to prevent the continued spread of this disease in the world as a whole."