DRUGS 2000
New Therapies for the Millennium
By Emily Bass

Forget power outages and computer crashes. HIV is the real millennium bug -- the one that will persist long after the lights have come back on. Sadly, there won't be a gift-wrapped surprise to stop the virus in its tracks under anybody's Christmas tree in 1999. For the time being, the ultimate miracle on 34th Street -- an actual cure for HIV -- is still just an entry on our wish list. Protease inhibitors simply aren't enough to rid the body of a virus that wedges itself into just about every nook and cranny of the immune system. Some critics even argue that we've lost valuable time these past three years by putting all our eggs, meaning research dollars, in the protease drug basket while ignoring other promising leads. But almost two decades of drug research have taught us valuable lessons about how and when to use existing therapies. They've also opened the door to exciting new crossover fields, yielding clues about other illnesses such as cancer, sexually-transmitted diseases, and autoimmune disorders.

Today, with so many targets and strategies to stop HIV and so many mix-and-match therapies, it's hard to keep pace with the field. As it stands, a determined if not-so-merry band of drug developers and researchers are racing off in different directions, some focusing on improved versions of existing therapies, others intent on exploring new chinks in HIV's armor. So what's the next best thing? Actually, there are several, from novel compounds to improved formulations and strategic recombinations of existing drugs to immune-boosting vaccines. Is any one perfect? Of course not. But even with their flaws, there's ample reason to keep hoping and working on a major breakthrough.

That said, veteran researchers and activists temper their praise of today's drugs with a rueful sense of lessons learned the hard way. "To the extent that protease inhibitors were heralded as the end of AIDS, we were too optimistic," says Spencer Cox, a firebrand activist with New York's Treatment Action Group, choosing his words carefully. "To the extent that they caused a revolution in the way people were treated-that ain't beans."

Summing up what many now feel, he adds, "We weren't too optimistic about the drugs; we were too optimistic about what they could do."

Stab In The Dark
The AIDS epidemic has taken such a toll and become such a given to most people that the pre-AIDS years sometimes feel like the distant past. But in the early 1980s, when the first cases of rare pneumonia began turning up in gay men in the United States, no one knew the virus existed. It took several years before HIV was identified as a member of the family of human retroviruses, newcomers on the viral scene. It later became clear that HIV is also a member of the subfamily of so-called slow viruses, or lentiviruses. Even now, fundamental aspects of HIV's nature remain mysterious. But in the early years, it was a virtual stab in the dark.

Back then, scientists scavenged the dusty shelves of drugs discarded by cancer researchers and combed the relatively young field of retroviral research for potential targets that might disarm HIV. It was a makeshift discovery effort guided by trial and error, hobbled by their scant knowledge of the virus and a lack of precedent about how to tackle a fast-moving, lethal epidemic with such a devastating scope. Add to that the stigma still attached to AIDS in many places, and government foot-dragging on funding for research.

These factors seriously hampered efforts to develop drugs but helped spawn a powerful activist movement that has continued to push for better and cheaper drugs-faster. "When you really think about it, this is the first virus that we've had any effective antiviral drugs against. I mean, there are one or two drugs out there for herpes and so forth, but on the whole we have never really had good drugs," says Neal Nathanson, M.D., director of the Office of AIDS Research at the National Institutes of Health. "A lot of good science happened in the early years, but I don't think anyone had a grand plan," says Jules Levin, executive director of the National AIDS Treatment Advocacy Project (NATAP), an activist who keeps close tabs on HIV research. "It's partially luck, partially hit-and-miss." The big difference is that now it takes a fraction of the time to fail or succeed.

Copycat Drugs
Ten years ago, scientists had what amounted to a child's sketch of HIV-and one could count the number of realistic targets for anti-HIV drugs on one hand. The main target was an enzyme called reverse transcriptase (RT) that acts a little like a Xerox machine, allowing the virus to make copies of itself inside the cell. The family tree of anti-HIV drugs reflects this simplicity: AZT, a recycled cancer drug that blocks reverse transcriptase, was the first drug the Food and Drug Administration approved for HIV in lightning speed in March 1987. All the approved drugs that followed have fallen into three categories, or classes: nucleoside reverse transcriptase inhibitors (NRTIs) like AZT; nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors that block HIV's exit from cells (see chart). There are also a handful of unapproved drugs in different categories, including Preveon, a nucleotide inhibitor of reverse transcriptase (NTRTI), and hydroxyurea, another dusted-off cancer drug. But that still leaves only two basic targets, RT and protease.

To date, each new class of drugs has buoyed hopes and, in one way or another, dashed them. In 1993, a large-scale, three-year drug trial, the Concorde study, proved what many had feared: AZT by itself (monotherapy) didn't slow the deadly course of AIDS. That finding was followed by reports of drug resistance to monotherapy and, later, the development of multiple drug-resistant strains of the virus. Meanwhile, people on therapies have had to cope with different side effects associated with each drug. Metabolic problems and liver disease linked to long-term use of highly active antiretroviral therapy (HAART) have forced some people to reconsider the benefit versus risk of these therapies. As if that weren't all, the latest roadblock concerns HIV latency, or the discovery of small but durable reservoirs of HIV inside dormant immune cells of people on HAART therapy that can't be reached with current drugs. These reservoirs could last up to 60 years, say scientists-in other words, a lifetime.

Needed: Simpler, Low-Cost Drugs
Today the treatment community is unanimous about one thing: The next generation of drugs must be more powerful and easier to take. They should also improve the problems associated with the present generation of drugs, such as resistance, dosing, absorption, and bioavailability (the active part of a drug that's available to fight the virus). "There is little reason to develop a novel drug unless it can be taken once or twice daily," says Steven Deeks, M.D., a leading HIV physician in San Francisco who has documented alarming rates of HAART failure among his patients, frequently because they have a hard time sticking to the complicated drug schedules.

Looking at the problem of resistance, it's now known that unless the virus is virtually eliminated from the blood-again, an unlikly prospect-it's only a matter of time before a viral mutant emerges that's resistant to therapy. Current estimates are that the virus mutates once each time it copies itself-up to one billion times a day. "It's like going to Las Vegas," says Thomas Merigan, M.D., director of the Center for AIDS Research at Stanford University. "HIV just keeps spinning its bases [its genetic building blocks], looking for a jackpot."

Now that we know more about HIV's building blocks, a more focused approach is being taken in drug development. About two years ago, the National Cancer Institute moved away from the time-honored method of random screening-an educated version of the trial-and-error method-to a targeted-discovery approach that builds on each new insight we gain about the virus and how it causes disease. "We now have the luxury of drugs that work and viral structures that are known," says Jonathan Kagan, chief of Drug Development and Clinical Sciences at the National Institutes of Health, who's hopeful that the shift will speed the discovery effort.

New Ally: The Immune System
What else is there to be optimistic about? Well, for starters, the crude sketch of HIV that yielded the first drug targets has given way to a more detailed portrait and multiple targets on the virus, as well as ways to help protect cells from infection. The early assumption that HIV takes a wrecking ball and totals the immune system has also turned out to be not quite right.

Instead, new studies show that, with some help from HAART, the body's immune resources can be restored and even boosted to possibly control the virus. That suggests an important role for novel immune therapies and even therapeutic vaccines. Long the stepsister of virology, immunology has stepped into the spotlight of HIV research, and scientists talk excitedly of "using the immune system as a drug," a concept put forth by Stefano Vella, M.D., a keynote speaker at the Sixth Conference on Retroviruses and Opportunistic Infections in Chicago earlier this year. Vella was referring to a paradigm shift that has taken place in our collective thinking about HIV-away from the goal of total eradication of the virus and on to HIV remission, or long-term control of HIV.

Historic Steps
To understand where we stand today, it helps to look back to the targets and therapies that have been tried so far. For every drug that's made it to market, hundreds of leads have failed to live up to their promise. Few people today recall AL-721, Peptide T, or soluble CD4, except the survivors of a period when, given the odds, it made more sense to try something than nothing. But as author and AIDS chronicler Mirko Grmek wrote so sagely in 1988, "All these recent efforts must await their own historian." In fact, drugs like Peptide T may yet have a role to play. A protein, Peptide T aims to block fusion, another critical step in HIV's life cycle, as does the new hotshot drug T-20. Ditto for soluble CD4, which could interfere with HIV's ability to infect cells, as do another promising class of compounds called coreceptor blockers. If you squint your eyes right when it comes to HIV drugs, it looks like history sometimes repeats -- and improves -- itself.

If the HAART era was the time when pharmaceuticals changed the way we think about HIV, the next millennium may be the time when HIV changes, once and for all, the way we think about drug development. The whirlwind wedding with protease drugs taught us that too-rapid drug approval comes with a human price-side effects and drug failure-and solidified the leap-before-you-look-too-hard school of thought. "It's not necessarily being done haphazardly, but when you approve drugs quickly, it takes longer to understand them," says activist Levin, summing up one of the trade-offs of accelerated drug approval.

So where does that leave us? With a host of experimental compounds that come, as new drugs do, with a range of caveats and wait-and-see promises. We've come a long way, it's true-and we've learned some surprising and disheartening truths about drugs in the existing classes. From where we stand now, between the hopelessness of the early 1980s and the dampened enthusiasm of what may soon be called the post-HAART era, it looks as if the best is yet to come. Of course, that will greatly depend on whether and how quickly the government and drug companies invest in promising but risky new approaches, and whether activists push them to do so.

Here, then, is a look at the family tree of anti-HIV drugs, with its budding branches.

Nukes: Firstborn Problems
No one said it was easy being a pioneer. When AZT broke ground in the field of antiretroviral therapy, it was almost inevitable that the drug would become a lightning rod for critiques and bitter disappointment. As the first drug to receive FDA approval for HIV, it was used alone (as monotherapy) for more than four years and served as a template for similar drugs in its class. "Nukes," or NRTIs like AZT, ddI, d4T, 3TC, and newcomer Ziagen, compete with cellular building blocks for places on HIV's DNA assembly line, acting like rogue Scrabble pieces, creating crucial "misspellings" that make it harder for the virus to reproduce itself. Using nukes as monotherapy, or in two-drug combinations, slowed the course of HIV-but only just. People continued to get sick, with no sign of the immune reconstitution that is now, in the HAART era, an important index of drug success. Although nukes have become important parts of any combination regimen, none, except perhaps Ziagen, pack the punch of a protease inhibitor.

Is it the drugs or the way they were used? A little of both. It's now known that no drug can be used as monotherapy, or resistance to the drug may quickly develop and prevent using other drugs in the same class. Since most nukes have been around longer than other drugs, they're more likely to have been used alone, or misused in suboptimal combinations. This long, checkered past means that many people may carry nuke-resistant viruses. But used correctly, the drugs still have potential, perhaps even as cornerstones of a nonprotease regimen using newer nukes Ziagen and pipeline candidates DOTC and DAPD. New studies show 3-nuke combos work as well as protease cocktails to stop HIV. As Merigan emphasizes, even with the oldest class of drugs, there's plenty to learn. "Abacavir [Ziagen] is a pretty good compound," he says. "We're not used to using it yet; there may be better ways to do it."

On the downside the oldest class faces new questions about long-term safety. In recent months, evidence has suggested that the drugs' dupe pieces of genetic material interfere with its normal ability to divide, which could lead to cancer (see sidebar, "The Trouble With Nukes"). "The recent NRTI discussion underscores the fact that long-term toxicities have not been well defined," says physician Deeks, adding a word of caution about nukes.

Nonnukes: Looking Good
If there is a Cinderella class of anti-HIV drugs, it may well be "nonnukes," or NNRTIs. With the recent approval of Sustiva, and more potent candidates in the pipeline, some experts have dubbed NNRTIs "the class whose time has come." Like nukes, they inhibit reverse transcription but with a different mode of action. NNRTIs fit themselves directly over important regions in the reverse transcriptase enzyme. Some NNRTIs also have potency that rivals that of protease inhibitors (PIs), and given the side effects of PIs, there's interest in using NNRTIs as the basis of first-line regimens. For researchers, the biggest question is how best to use these new tools. "Nonnukes are good drugs," says Merigan. "We really need to know whether to use them as first- or second-line therapy." This also means figuring out the best way to use NNRTIs in combination with other drugs. Are two NNRTIs in a single regimen better than one? Will the two drugs compete and actually cancel out their potency?

Once again, the biggest stumbling block is resistance. A single viral mutation called K103N can create cross-resistance to most drugs in this class. Newer drugs are designed to work against viruses with this specific mutation. But there are also reports of new mutations arising from nuke-nonnuke combinations and concerns about as yet unknown long-term effects. For now, nonnukes are a valuable option, both in protease-sparing combos for people just starting therapy and as salvage options further down the line.

Protease Inhibitors: A Dead End?
Leader of the pack or sitting duck? With their overwhelmingly positive effect on the course of HIV disease, protease inhibitors have done more to change how people think about HIV than any other class of drugs. Still, most people are far from starry-eyed over these four-year-old meds, and if you listen closely, you may even hear sacrilegious whispers asking: Does this class have a long-term future?

The answer, for now, is yes. In the next year or two, new and better protease inhibitors are likely to get FDA approval. Some, like tipranavir (see sidebar), may even be an option for those with PI-resistant viruses. Many advocates believe that the drug companies are feeling the pressure to produce something new. "Part of what shapes this is market forces," say TAG member Cox. "We won't see a lot of me-too PIs because people can't or won't use them." Others argue that it's easier and cheaper for drug companies to modify PIs than pursue other, riskier avenues, so we should expect yet more slightly different third-generation me-too PIs.

Like reverse transcriptase inhibitors, protease drugs came about in large part because their target was familiar, which also made them financially attractive to drug companies. Protease, or proteolytic enzymes, work like a fleet of miniature chemical chainsaws that cut up and package proteins found throughout the body. The protease active in HIV is called aspartic protease, an enzyme that puts the finishing touch on newborn particles, or virions, as they are being launched off the surface of an infected cell.

When researchers went looking for new HIV targets, they already knew how to target a different type of protease using a class of drugs called renin inhibitors, so it wasn't that much of a step to block HIV protease. This familiarity and the surprising potency of the drugs fueled their rapid approval. "This was extremely important [to drug companies] from a drug development standpoint," explains Carl Dieffenbach, associate director of the Basic Sciences Program at the National Institute of Allergy and Infectious Diseases (NIAID).

By now, the headlines trumpeting the success of protease inhibitors are old news, replaced by a growing concern over their toxicity. There's no doubt the drugs work to stop HIV, even in people who are quite ill, but at what price? Liver failure? A heart attack? As scientists try to understand what causes PI side effects, they're also learning from early mistakes. The first protease trials simply added the drug to existing combinations-a guaranteed recipe for resistance. "There's been a lot of inappropriate use of protease inhibitors," says Eugene Sun, M.D., head of antiviral ventures at Abbott Laboratories. "We've learned how not to use them."

Drug delivery is another major stumbling block for protease inhibitors. To arrive at a viral target, all drugs move through a protein-rich thicket of plasma, the liquid component of blood. Proteins are sticky substances that latch on to other compounds and impair their function. Early PIs acted like protein sponges and were nearly useless in fighting HIV. Although reformulations have greatly improved PI delivery, they've left us with large pills taken by the handful to achieve the necessary dosage. Even with constant revisions and updates, the drugs continue to have a major impact on the liver and kidneys, and this is likely to take its toll. "The current drugs are not great," says Abbott's Sun bluntly.

There's also been debate about whether this late-stage attack on the virus is an ideal strategy. PIs attack newly formed virus particles, or virions, as they're budding off infected cells. The drugs don't block the creation of genetic mutants of the virus, which occurs during an earlier stage. This may give the virus an edge over protease inhibitors. On the other hand, some scientists believe that PIs could have unexpected positive effects on the immune system that go beyond fighting the virus. "It could be that the immune system chews up dead virions and responds to them," suggests Dieffenbach of NIAID. "You may be getting an immune boost from them."

Après Y2K, What Now?
Too much has been learned about the virus and its ability to hide and mutate to rest easy with what's in today's medicine chest. An alternative strategy involves designing drugs that interact with infected cells as opposed to the actual virus. "We've come full circle," says Amy Patrick, Ph.D., head of virology at Agouron Pharmaceuticals. "Early antiviral drug-design efforts paralleled research on treating cancer, and then focused on finding new virus-specific targets. Now we're back to asking, how can we inhibit the host-gene functions?" New techniques mine our knowledge of cells, genes, and viral assembly. Since many of these novel agents go after different targets than those used by existing drugs, they should be active against today's drug-resistant virus.

Rising Stars: Coreceptor blockers
One hot area of drug research is aimed at ways of preventing HIV from entering cells. To understand what that means, think of a lock on a door. Coreceptor blockers bind to sites, or doorways, on the cell surface that the virus uses for attachment and entry. In other words, they jam the lock. The two coreceptors receiving the most attention are called CCR-5 and CXCR4. Initial interest in these compounds grew when it was discovered that some people who had a genetic defect in CCR-5 appeared to be fully or partly resistant to HIV. Since that time, other doorways have been discovered. Some scientists worry, however, that blocking one door-CCR-5-will only lead HIV to choose another-CXCR4. Unfortunately, the latter is usually associated with more virulent strains of the virus. At least 50 percent of people who progress to AIDS eventually develop viruses that use CXCR4. However, many experts, including coreceptor researcher John Moore of the Aaron Diamond AIDS Research Center, believe that we may be overestimating the risk of receptor-switching, particularly if a strong CCR-5 blocker is found. "It's a gut reaction that this is going to happen," he says. "Maybe the gut's not quite right." Moore and others theorize that there may actually be a negative selection pressure that prevents the emergence of viruses that use the CXCR4 doorway.

There's also the possibility that the virus could bypass both coreceptors and adapt to using other docking sites all together. It's also unclear how toxic a combo of agents that block the CCR-5 and CXCR4 doorways might be. At this year's insider-track Gordon Drug Conference in California, coreceptor blockers were all the buzz-until things got serious. "Drug companies were talking, [all] excited, and then it was like an iron door came down," says NIAID's Dieffenbach, a conference cochair. "The race is on."

The Dark Horse
This winter a novel anti-HIV approach that developers are calling "protein therapy" enjoyed 15 minutes of fame-perhaps a sign of things to come, perhaps a flash in the pan. Also known as the "trojan horse" strategy, this approach uses innovative packaging to smuggle proteins that are up to 200 times bigger than current drugs across the cell membrane. If coreceptor blockers fiddle with locks and keys, protein therapy aims to walk through cellular walls carrying its antiviral weapon. The advantage to larger protein molecules is that they are much more specific, zeroing in on a single reaction or target with precision. In this case, a team led by Steven Dowdy, an ebullient Howard Hughes professor at Washington University in St. Louis, has chosen Caspase-3, a protein that responds to a specific stage in HIV replication by triggering cell suicide.

"If you've never read any of my papers, the first response would be '...and if pigs had wings,'" says Dowdy. Indeed, some researchers point out that since Caspase-3 only recognizes actively infected cells, there will always be virus particles that escape before cell suicide takes place-sort of like closing the barn door after the horses (or pigs) have escaped. "Current HIV strategy is basically trying to put the brakes on a train that's going downhill," says Dowdy. "Why not exploit the viral protease enzyme and allow it to roll down the tracks and crash?" He adds that, theoretically, protein therapy could be used to fight hepatitis C, malaria, and other infectious agents that use a protease as part of their lifecycle. Caspase-3 is still in animal trials.

Arming Cells
Long favored as the ultimate solution to many illnesses, including heart disease and cancer, gene therapy offers the tantalizing possibility of arming a cell for life by changing its genetic makeup. So far, gene therapies aimed at making cells immune to HIV have been slow to develop. The biggest problem is delivery. It's almost impossible to get genes into 100 percent of cells at exactly the same concentration, the condition required for effective gene therapy. Julianna Lisziewicz of the Research Institute for Genetic and Human Therapy has spent years working in the field. "I think the only way this problem can be solved is if we can put genes into stem cells," she says, referring to a cell type that is often called "the mother of all cells" because it gives birth to the many specialized cells of the body. "And even with that, we're still not efficient enough." Lisziewicz is more hopeful about gene therapies that help boost immune response to the virus and could potentially serve as a vaccine strategy.

The Late Bloomer
In the great pageant of medicinal breakthroughs, integrase has been, well, a no-show. Long hailed as the next big thing in anti-HIV drugs, integrase inhibitors have been long in coming, in part because scientists were stymied by the enzyme's tendency to bind to itself and form solid crystals that hopelessly obscured its structure. Finally, this year a team of scientists at Merck Laboratories figured out the three essential steps that the integrase enzyme performs. This major breakthrough was then offset by the nearly simultaneous realization that the most effective time to block integrase is when it's bound to viral DNA. Before they can develop a drug that might stop integrase from working, researchers will have to get an exact 3-D image of the tightfisted grip that forms between the convoluted, pocked, shape-shifting protein and the viral DNA. Daria Hazuda, a Merck chemist who has spent the last five years working on integrase, says it's extremely difficult to figure out the structure of the enzyme when it's bound to the substrate [viral DNA]. "That's one of the things that keeps me up at night," sighs Hazuda.

The Swat Team
Another promising area of research involves HIV genes such as nef, rev, tat, gag, pol, env, vpr, vif, and vpu that could play a key role in creating vaccines. These are also the names of the "accessory" proteins they code for. The proteins act as viral Green Berets with specialized missions that go beyond assembly and packaging, and appear to be toxic to cells at surprisingly low concentrations. Nef- and tat-deleted viruses are being tested in vaccine studies. They can trigger an immune response to the virus without causing disease. But so far, no candidate seems entirely safe. Robert Gallo, M.D., codiscoverer of HIV, is especially excited about the tat gene, which he hopes to use in a vaccine. In lab studies, antibodies to tat block HIV replication. Human studies using a tat toxoid look promising. We may still see the development of drugs targeting specific genes or gene products, particularly as new research and better tests improve our understanding of these behind-the-scenes players.

Hide and Seek
With so many areas of HIV infection still a mystery, treatment activists and researchers are also paying close attention to aspects of the disease that current therapies fail to address. For starters, there's latent infection, the phenomenon that originally stole the thunder from the promise of a cure. It's now known that HIV ducks below the immune-system radar by stowing away in dormant cell reservoirs of lymphoid tissue and protected sites like the brain. Now a new theory, put forth by virus hunter Ashley Haase at the University of Minnesota, suggests that the virus may spread between nondividing cells, perhaps using a molecular underground railroad to make its way from one apparently locked house to another. If this is the case, then there may be whole realms of viral activity that will have to be mapped and blocked by as-yet-undiscovered drugs.

Even without cell-to-cell spread, latent viral reservoirs remain a critical obstacle to long-term control of the virus. To effectively target these reservoirs with drugs, some researchers believe they need to understand them better. But to do that, they have to be able to find them. Right now, we lack a simple, sensitive screening technique to detect these hidden viral reservoirs.

Today researchers are testing Interleukin-2, an immune booster, to see if it can flush out virus from the latent reservoir. Other interleukins are also being investigated as potential therapies.

Future Gambles
The big question mark on the horizon is whether immune-based therapies and vaccines could be used as complementary approaches to antiretroviral drugs. At last count 36 vaccines were being tested in U.S. clinical trials, some for both therapeutic and preventive uses. This means they could help HIV-infected and unifected people. Several DNA-based vaccines look especially good. In small studies of primates, they induced protective cellular-immune responses to genetically engineered SHIV viruses made of an HIV envelope and a core of the simian immunodeficiency virus. These vaccines don't eradicate the virus but contain active infection. As such, they represent a working model for HIV remission.

Over at the Yerkes Primate Research Center in Atlanta, Harriet Robinson, M.D., found that a DNA vaccine combined with a fowl pox, or bird virus booster, could elicit cellular-immune or CTL (cytotoxic T-lymphocyte) responses that protected macaques for more than 62 weeks. The vaccine significantly reduced the level of virus replication. After vaccination, the macaques were repeatedly exposed to or "challenged" with virus, and each time they mounted a "memory" T-cell response. This suggests, at least theoretically, that such a vaccine might contain rebounding viruses in people on therapy who have undetectable virus levels. The same thinking applies to the sexily named Co-X-Gene, a "naked DNA" prime-boost vaccine, now entering human trials in Australia. Studies by Stephen Kent, M.D., show the Co-X-Gene protected macaques against active infection. Best of all, the vaccine is very cheap-just a few pennies per shot-and doesn't require refrigeration, so it's ideal for use in the developing world.

There's also interest in Remune, also known as the Salk Immunogen, which is being tested in combination with antiretroviral regimens in human trials. Early studies showed Remune can boost HIV-specific immune "lymphoproliferative responses" (LPR) that appear crucial to controlling HIV. But a big Remune study involving 2,500 people was just ended because the drug didn't seem to help (or hurt). Researchers are looking to see what happens to people on therapy who receive Remune and later abandon therapy altogether. The hope is that the vaccine will help control any outbreak of the virus.

HIGH STAKES FUTURES
Discovering new drugs is only half the battle. A chorus of global activists reminds us that progress must extend beyond the lab bench. New discoveries will be worthless if they can't be used by the people who need them most -- growing numbers of women, children, and the poor. Today's imperfect array of life-saving HIV therapies are available to a mere 10 percent of the world's HIV-positive population, which numbers tens of millions. Power may flicker as the world rolls over into Y2K, but for everyone affected by the AIDS epidemic, it will also be time to see if new lights are turned on at the end of a very dark tunnel.

Senior Writer Emily Bass wrote about pediatric HIV in our September issue.