Newsday - February 7, 1999
Laurie Garrett - Staff Writer

There are no crucial advances foreseeable in the next five to 10 years with the potential to slow expansion of the global epidemics of HIV, drug-resistant tuberculosis, dengue fever or malaria, scientists say.

"We're on the verge of the 21st Century with all this modern technology," says Larry Gostin, a professor of law at Georgetown University and expert on AIDS and human rights, "and yet we're as vulnerable to pathogens as we were decades ago."

Perhaps the best example of this is AIDS. As the numbers of AIDS cases and deaths in America continue their sharp decline since 1994, it's tempting to view the epidemic's future optimistically. But experts interviewed during the past two months have outlined a disturbing two-tiered future in which, lacking a vaccine, the disease continues to grow at an alarming rate among the poor in both the United States and throughout the world, exacting huge tolls on society in most Third World countries.

This gloom may come as a surprise to those familiar with recent HIV treatment developments involving combinations of three or more anti-viral drugs. Called HAART, for highly active anti-retroviral therapy, the treatment has revolutionized HIV care since being introduced in summer 1996.

But as the 21st Century dawns, experts say that HAART is clearly not the answer for all: Its price tag alone - $10,000 to $60,000 a year for the drugs - renders the therapy inaccessible for more than 90 percent of the world's HIV-infected population, now estimated by the United Nations AIDS Programme at 33.4 million people.

Even in North America and Western Europe, where hundreds of thousands are currently on HAART, trouble is brewing. Many - about 50 percent, depending on which studies are cited - fail their initial rounds of therapy because they can't tolerate its toxic side effects or adhere to its rigorous daily dosage schedules. And missed doses promote emergence of drug-resistant viruses, allowing the HIV infections to swell and sicken the individual.

Finally, there is a realization that what was initially whispered about as a possible cure is now seen as no more than another difficult palliative, a treatment that keeps symptoms at arm's length. In 1997 and 1998, studies found evidence of vast, hidden reservoirs of HIV in successfully treated patients that experts now say will still plague the patients 25 to 30 years down the road.

Worse yet, it now appears that these reservoired viruses continue to reproduce and even mutate, despite seemingly effective HIV treatment.

"There's ongoing replication and cell-to-cell infection even in the presence of HAART," explains Dr. Mario Stevenson of the University of Massachusetts in Amherst. "So it may not be [HIV] latency. It may be continued viral production. And how that occurs in the face of effective drugs is a mystery. All we know is the pattern: continued low-level replication and virus evolution."

Dr. Emilio Emini, of the Merck Research Laboratories in West Point, Pa., says time remains the major enemy of people with HIV. "There are patients who, even though they've suppressed virus for years, will fail," Emini says. "So what does that tell you? It tells you it's not an easy consideration to quote-unquote cure a patient. Even after a long time of suppression . . . the virus will cycle up."

SO IS THERE a solution?

Experts hold out little hope of a final cure, differing significantly in their outlook only on one point: How many decades will pass before an effective, affordable vaccine is developed for use worldwide?

"We've said from the beginning this is a nasty little virus," Emini says. "My fundamental hope is that in the end we'll be able to make a sincere shot at a vaccine here."

The National Institutes of Health also has reached the conclusion that a vaccine is the only thing that can slow HIV's seemingly relentless expansion. Currently, half the agency's $1.8 billion HIV budget is aimed at the search for a vaccine, says Neal Nathanson, director of the Office of AIDS Research.

"We're in it for the long haul," he says. But he argues that the private sector lacks similar long-term commitment to the problem: "None of the big players [the world's large pharmaceutical firms] are seriously involved in developing a vaccine at this time," he says. "They don't see the profit in it."

At Glaxo Wellcome, the largest multinational pharmaceutical company and a major player in HIV drug development, Peter Young, the vice president for HIV therapeutics, only shrugs: "I think we're probably as far away from treatment cures as we are of vaccines."

One problem is that each time the virus population cycles up, that means it's managed to mutate to resist one or more of the HAART drugs. Doctors then must change the patient's combination, drawing from a list of more than 250 drug triads currently licensed in the United States. But most mutations confer HIV resistance not only to just one individual drug, but also to that entire class of drugs.

So each new HAART combination lasts for less time than its predecessor, and eventually patients run out of treatment options as their highly resistant viruses overwhelm the body, explains Dr. Michael Saag of the University of Alabama.

"So now we've evolved from a cure paradigm back to a palliative care one," Saag says. "Perhaps the biggest difference . . . is we now should expect failure with whatever [combination] we first use." WITH THE BLOOM clearly off the HAART rose, AIDS advocates are calling for rapid development of drugs that hit novel targets on HIV, possibly outwitting the virus' awesome mutation capacities. But Emini says there isn't much in the drug development pipeline, and it's "impossible to answer" when such novel agents might be ready.

"Where will we be in 10, 20 years?" asks Dr. Peter Piot, the director of UNAIDS. "It's really, really hard to say. We haven't done [forecasts] going out more than to 2005. We've learned that the projections turn out to be awfully wrong."

Wrong, in that the epidemic has consistently outpaced worst-case scenarios.

The key question for forecasters, experts say, is the proverbial bell-shaped curve. Most, if not all, epidemics start at a low level, rise rapidly and then naturally slide back down the bell-shaped curve as society responds, ending up permanently at a modest endemic level in the population. The reasons for that downward curve are multitudinous and vary from epidemic to epidemic. But the curve is always there.

Is there evidence of a bell curve for HIV? Piot believes that HIV has hit the top of its bell in some hard-hit African countries, such as Uganda, Tanzania, Zambia and Zimbabwe. But the top of that curve was reached only after upwards of a third of all adults under 50 years old were infected, he pointed out.

The first community to reach an HIV bell curve was San Francisco, where the bell peaked in the mid-1980s with the infection rate exceeding 50 percent. Now, due largely to education programs in the gay community, the disease claims less than a fifth of the San Francisco gay population.

For more than a decade, epidemiologist Jim Chin executed HIV forecasts for the World Health Organization and UNAIDS. Now retired and living in California, he believes that "there will continue to be from 25 to 30 million persons with HIV alive each year for the next 25 years."

By then, he says, "hopefully, the African countries can get their act together and begin significantly reducing their annual incidence of new infections so that 50 years from now . . . the global prevalence will begin to drop to about 10 to 20 million - with well over 95 percent in developing countries and the vast majority [80 percent or more] in Africa."

Grim as that scenario may be, Chin concedes that India, with a population of nearly 1 billion people, is the "wild card" that could throw off the forecasts. It's one thing for Botswana, with 1.4 million people, to have a 32 percent infection rate among young adults; it's quite another for 32 percent of young adult Indians, or about 200 million people.

A recent joint publication of the World Health Organization, Harvard School of Public Health and the World Bank, entitled "Health Dimensions of Sex and Reproduction" predicted that much of Africa wouldn't see its HIV epidemic peak until 2005 to 2010. Asia's epidemics, the paper said, wouldn't peak until a decade later.

If true, and if an adult infection rate higher than 30 percent indeed constitutes society's HIV bell peak, the world could have nearly half a billion people living with HIV and AIDS by the year 2020.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, says it is figures like these that have prompted his agency to target half of its HIV spending toward vaccine development.

Fauci is more optimistic than many experts that an acceptable vaccine will soon be developed. "We may not get a perfect vaccine within a decade," he says. "But I'll bet you a Sicilian pizza that we have some form of moderately effective vaccine [against disease progression] within a decade."

THE EXACT TIME frame for vaccine development remains a point of debate for the experts.

Immunologist John Moore of the Aaron Diamond AIDS Research Center in Manhattan, for instance, says that forecasts of 20 years are "pessimistic by a factor of two - I hope." But Nobel laureate Dr. David Baltimore, who heads President Bill Clinton's HIV Vaccine Committee, says "30 years is a reasonable estimate" for development, testing and practical use of a preventive vaccine.

"It's a heck of a plague," Baltimore concludes.

But it's not the only problem faced by medical experts dealing with infectious disease. The helplessness felt in the face of HIV is mirrored in battles against a host of bacterial and parasitic diseases, many of which are either not treatable or, for a variety of reasons, are not being properly treated. And so ancient scourges, such as malaria and scarlet fever, continue to account for nearly half of the world's population that dies annually.

Dr. Bernard Pecoul, of the humanitarian organization Doctors Without Borders, is convinced that a key solution is lowering the cost of essential drugs for poor countries.

If the world's top pharmaceutical companies follow their current cost trajectories, "they will end up only focused on the 300 to 400 million people in the richest countries," he says. "We cannot accept that, for most of the world, the essential drug list is now things from the 1950s and '60s, many of which cause drug resistance."

What's at stake? "A timebomb," Pecoul warns, of resurging infectious disease - strengthened by drug resistance - that will explode not just in the world's poorest countries, but in Europe and America as well. "The global village will be affected," he says.

Indeed, a forecast by researchers at the University of California in San Francisco predicts that by 2070, the world will have exhausted all antimicrobial drug options, as the viruses, bacteria, parasites and fungi evolve complete resistance to the human pharmaceutic arsenal. It is a vision that remarkably is shared by many of the world's top microbiologists and infectious diseases experts.

"People are looking at new targets for antimicrobials," Dr. Stanley Falknow of Stanford University says. "But it's not clear they will work."

Although several laboratories are working on novel ways to kill bacteria and viruses, Falknow says, no fundamentally new approaches are expected to be available within the next 10 years. And if such drugs do reach the marketplace they will undoubtedly follow the financial pattern set with antibiotics: Each newer drug costs far more than its predecessor. And the newer agents are usually more toxic, their use fraught with fiercer side effects.

"The biggest concern is staphylococcus, where only one drug is left," Falknow says. "If that were incurable it would be devastating," because the bacteria, which cause a wide range of life-threatening diseases, are highly contagious.

Fauci warns that mutated microbes resistant to hosts of drugs are the real crises looming for the 21st Century. "There is more of a chance of a virulent influenza A wiping out whole populations than you and I getting a gene card," he says, referring to cards that would contain a person's genetic code.

The drug companies, meanwhile, are banking on vaccines. They say innovative products, such as vaccines made from the DNA of viruses or bacteria, will be available for tuberculosis, malaria, the diarrheal disease schistosomiasis and other killers within 20 years. And, they say, these vaccines will be affordable.

But Dr. Phillip Lee, former second-in-command at the U.S. Department of Health and Human Services, says he's heard that before. "Here we are, 100 years after Pasteur identified the cause of rabies and [Robert] Koch the cause of tuberculosis," Lee says. "Yet we did more to control TB by social factors" than by any vaccine, and today more people globally die of tuberculosis than in Koch's day.

"One hundred years out," he says, "and we still don't have a vaccine for tuberculosis or malaria."
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