BATTLING THE AIDS VIRUS

By Christine Gorman

MAGIC JOHNSON DEMONSTRATed last week that being infected with the AIDS virus no longer prevents one from living an active life. Medical science has made steady progress in the 15 years since AIDS appeared in the U.S.--most dramatically in treating the devastating secondary infections in the later stages. There is still no cure, and a vaccine is nowhere in sight, but hardly a week goes by without some advance on the AIDS front.

Last week was especially encouraging; several major findings were issued that not only promise to help HIV-positive patients live longer and healthier lives, but could also point the way to future advances. At a Washington gathering of top AIDS experts, researchers were energized by a series of dramatic announcements. Chief among them:

News from Abbott Laboratories that an experimental drug called ritonavir cut in half the death rate for a group of patients suffering from advanced AIDS--at least during the seven-month period of the study.

A report from Merck that a second drug, indinavir, used in combination with two other drugs, AZT and 3TC, reduced the levels of HIV in the blood of 24 patients an unprecedented 1,000 times.

Both ritonavir and indinavir belong to a promising new class of drugs called protease inhibitors, which block production of a key enzyme, protease, that the virus needs to replicate itself. It was only last December that the U.S. Food and Drug Administration approved the first protease inhibitor, Hoffmann-La Roche's saquinavir. Ritonavir and indinavir could get the FDA go-ahead--and reach doctor's offices--as early as this summer. "The data are as good as anything I've seen," says Dr. Anthony Fauci, a leading AIDS expert at the National Institutes of Health.

Much remains to be done. There are serious concerns over how much the drugs will cost and whether they will be in short supply. Moreover, it is still not clear just how long they can prolong life. But for the first time doctors may have at their disposal an arsenal of weapons that can battle the virus at virtually every stage of its life cycle--not just in the final days but from the earliest months after infection. Says Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology in San Francisco: "It seems as if the tide is turning a little bit in our favor."

Just the idea that HIV can be treated in its early stages is surprising, given what was, until quite recently, conventional wisdom about AIDS. For years scientists portrayed HIV as a shadowy saboteur that invaded the body and then immediately went into hiding, staying dormant for a decade or more. Indeed, the first stage of infection seemed so quiet that some people questioned whether HIV was truly the cause of AIDS.

It turns out, however, that the body and the virus engage in mortal combat from the beginning. The main battlefield is not the circulatory system (where physicians had been looking for the virus, dutifully taking blood samples every few months) but in the hard-to-reach lymph nodes. Now scientists realize that there is a window of opportunity, and a fairly large one at that, to attack the virus while it is still hiding, before it has started to wreak havoc on the body's natural defenses.

Scientists have known almost from the beginning that AIDS is a disease of the immune system, invading and destroying the white blood cells that fight infection. But only in the past few years has it become clear that the disease progresses in three distinct and very different stages.

The first stage is over so quickly it can easily be missed. Within days after the virus has penetrated the body, many people develop what feels like a miserable case of flu. No wonder. Thousands of HIV particles are reproducing themselves in their favored target: a specialized group of white blood cells called helper T cells. These cells, also known as CD4 cells, are the linchpin of the immune system, and when they are attacked the body marshals all its resources to protect them.

David James Wright, 38, of Los Angeles remembers the feeling vividly. One evening in 1983, around midnight, he began sweating profusely. Soon, a red rash covered his body and he had trouble breathing. A friend rushed him to an emergency room, but nobody could determine what was wrong. "I was shaking violently," he recalls. "It was a nightmare." Nine days later, however, he felt fine. It was only years later, when he fell seriously ill, that he realized what had happened.

The second and longest stage begins after the body has successfully swept the virus from the blood and trapped it in the lymph nodes. HIV doesn't lie dormant, however. It still churns out copies of itself. But the damage is limited because the immune system has activated two powerful defense mechanisms: antibodies, which surge through the blood neutralizing any HIV particles that seep out of the lymph nodes, and a second group of specialized white blood cells, called killer T cells, which attack and destroy infected tissue.

This is the stage at which most people discover they are HIV-positive, thanks to an antibody test developed in 1984. Raul, 25, of East Los Angeles, learned he had the AIDS virus two months ago, after a sore throat sent him to a doctor. Like so many others who discover that they are HIV-positive at the earliest stages, Raul found it hard to believe he could have a life-threatening disease and still feel so healthy. "I've thought about it, but I just can't picture it happening to me," he says. "I think I'll probably die of something else."

There's a chance that he is right. In some people the second, mostly asymptomatic stage stretches out for a dozen years or more--or perhaps, in rare cases, indefinitely (see following story). But for the majority, the reprieve lasts only five or 10 years. Each year more HIV escapes from the lymph nodes into their blood. The immune system gets progressively weaker as more and more helper T cells die.

The third stage of infection begins when the helper T-cell count drops from an average of 1,000 cells per milliliter of blood to fewer than 500. Doctors tend to treat that number as an imaginary tripwire. When a patient hits it, they issue a prescription for AZT, the original anti-HIV drug and still the most widely prescribed. Unfortunately, AZT by itself is only marginally effective. The virus is notoriously changeable. Within 18 months, it usually manages to mutate into a form that is no longer susceptible to AZT or any of its chemical cousins: ddI, ddC and 3TC.

The official diagnosis of AIDS generally is not made until the helper T-cell count falls below 200. That customarily marks the beginning of a patient's final decline. In the past few years, however, doctors have come to realize that the T-cell number doesn't really tell them how sick a person is. Patients with fewer than 200 helper T cells sometimes seem quite healthy, while others with a higher count are already suffering from opportunistic infections, like Kaposi's sarcoma or pneumocystis pneumonia.

The difference between the two groups of patients, scientists now believe, can be traced to the amount of HIV that has escaped from the lymph nodes. Researchers have only recently learned how to measure that level, and according to a report presented in Washington last week, it seems to be a more accurate gauge of the progress of the disease. It can also predict survival. In a study of 181 HIV-positive patients, 65% of the subjects who began the study with 34,500 or more virus particles per milliliter were dead within five years. By contrast, all the subjects whose viral load was fewer than 5,000 particles survived. The hope is that when virus-testing kits become widely available, doctors will be able to judge accurately which patients are doing O.K. and which need aggressive therapy.

With the advent of the new protease inhibitors, researchers find themselves in a dilemma. Given what they know about how and when the virus reproduces, it makes more sense to try to attack HIV sooner than later. But they also know that if they don't hit it hard enough, the virus will mutate into a resistant strain. That's why drugs are given in combination--so that a virus resistant to one drug might still be wiped out by one of the others. But there are preliminary indications that viruses resistant to protease inhibitors may have already started to appear. "Don't believe anyone who tells you we are not flying by the seat of our pants," says Dr. Harvey Makadon of Beth Israel Hospital in Boston.

Even if protease inhibitors live up to their potential, it's not clear who will be able to afford them. By some estimates, the new drugs will cost $500 to $600 a month--probably for the rest of a patient's life. That's on top of standard treatment with AZT and its cousins, which runs approximately $400 a month. Hospitalization and other medical care in the final stages of the disease can add $150,000. Future treatments could dwarf even that. "Where is this going if we don't wake up?" asks Dr. Max Essex of the Harvard AIDS Institute, who believes a larger share of resources should be directed to developing vaccines.

Where will all this money come from? In an era of managed care, insurers are loath to take on additional liability. Government funds are drying up too. Beginning last month, budget cuts for New York State's drug-assistance program, for example, forced it to drop from 196 to 66 the number of reimbursable medications used by AIDS patients.

It may well be that the more sophisticated and effective HIV treatments become, the fewer people will have access to them. This grim new calculus is painfully apparent to Patrick Roll, 41, of Boston, whose T-cell count has dropped below 50 and who takes nine capsules of the protease inhibitor saquinavir each day. Considering that he first tested positive in 1983, he is in remarkably good health. "I'm from a socioeconomic group that had careers," he notes. "We've been able to keep our insurance or afford to take it on ourselves." Not everyone is as fortunate as Roll. Or, for that matter, Magic Johnson.

--Reported by Sam Allis/Boston, Hannah Bloch/Washington, Jenifer Mattos/New York, J. Madeleine Nash/Chicago and Tara Weingarten/Los Angeles

With reporting by SAM ALLIS/BOSTON, HANNAH BLOCH/WASHINGTON, JENIFER MATTOS/NEW YORK, J. MADELEINE NASH/CHICAGO AND TARA WEINGARTEN/LOS ANGELES