Newsday - December 12, 1996
Laurie Garrett - Staff Writer

Sharp, director of the HIV Comprehensive Care Center at Beth Israel Hospital in Manhattan, is one of the world's most experienced AIDS clinicians. And yet she's the first to admit that when it comes to contemporary combination-drug therapies for HIV, "Boy, it's complicated stuff!"

In grand rounds with her staff at at the hospital , Sharp tells the assembled 15 health professionals, "We're going to have to develop our own expertise" because no one really knows how to use the complex therapies that recently became available for patients in all stages of HIV infection, from the asymptomatic to those dying with full-blown AIDS.

After years of offering only palliative therapy to their patients, doctors like Sharp feel for the first time that they have drugs that promise genuine - maybe even lasting - benefit. And they have choices - about 120 possible combinations, in fact - that allow them to mix up to 10 different drugs to best fit their patients' conditions.

But for all they've gained in treatment options, Sharp and other doctors are acutely aware of the risks and uncertainties associated with the drugs: No one's sure when it's best to start therapy; the side effects can be severe, and some patients can't comply with a life-long regimen that could include taking as many as 36 pills a day.

Clinicians are looking to the drug companies, the U.S. Food and Drug Administration and the National Institutes of Health for guidance. Several federallyappointed committees of top scientists and doctors are meeting in an attempt to hammer out treatment guidelines.

But there, too, lies uncertainty. "Our clinical experience in the use of these drugs is still very limited," says Dr. William Paul, director of the NIH's Office of AIDS Research. "Similarly, the types of experimental trials that could provide the information [doctors] ask for are only now beginning."

The questions physicians have are numerous. Key among them is the significance of viral-load tests. In some patients, the new combination therapies have pushed extremely high viral loads below the limits of detection that current technology can measure, but scientists aren't sure what that means.

In practical terms, that limit is 200 viral particles per droplet of blood, or 1 million in the body (anything above those levels can be detected). But does that mean there still are 1 million viruses in the body? If so, scientists say, it is virtually a giventhat any failure to adhere to medication therapies will give HIV the chance to surge into the bloodstream.

Or is it possible that zero detectable viruses is, at least for some patients, the same thing as absolute zero - with all HIV eradicated from their bodies? None in the blood, none hidden in lymph nodes or tissues, none lurking anywhere to threaten an individual's life.

Uncertainty is always a companion of medicine, and good doctors know that there is as much intuition and artistry in healing as there is hard science. Ask anyone who treats cancer patients.

The problem lies in the fact that protease inhibitor and non-nucleoside reverse transcriptase inhibitor drugs were licensed only in the past 12 months by the FDA. And that was largely based on clinical experiments in which only a few participants took part in any trial that entailed taking the drugs for more than a year. Further complicating matters, only a handful of the 120 possible combinations of these drugs has been formally tested. So, of the estimated 175,000 to 250,000 Americans on these drugs only some are living, breathing experiments taking previously untested therapeutic cocktails.

At grand rounds, Sharp and her staff discuss a young actor who failed to turn up for his viral-load test and missed a third of his recent medical appointments. Without the viral-load data, they're flying blind - giving powerful drugs to the patient without knowing whether those drugs are effective or whether the patient is taking the medicines as prescribed.

"What's the psych work-up on this guy?" Sharp asks.

THE TEAM psychiatrist says the man suffers from severe depression - so serious that he occasionally descends into such dark bouts that they leave him unable to get out of bed for days. And the staff psychological counselor adds that the man may not be taking his drugs during these bouts.

Should that depressed actor continue on the drugs? Yes, they decide, for now. But they need that viral-load test as soon as possible. What about the 28-year-old crack addict who missed all but two appointments and was given triple-combination drugs? He's disappeared. It's a moot point.

Such are the vagaries of modern HIV care. It's so complex, Sharp says, that a law should be passed allowing only AIDS-specialized doctors to prescribe these drugs. After all, she argues, primary-care doctors can't give out cancer chemotherapy drugs - only board-qualified oncologists can dispense drugs for cancer. And today, HIV care is at least as complicated as cancer treatment.

"There are too many combinations and permutations of drugs, viral, immunological and prior drug-treatment history issues to have clinical trials to answer every situation," says Dr. David Feigal, chief of the FDA's antiviral division. "But I think there are some things that we know very clearly. Some drugs . . . have produced survival benefits [so people live longer]. Some combinations have particular potency. And the best shot at treatment is the initial therapy."

But which initial therapy? And when should therapy begin: during the earliest asymptomatic stages of infection or later, as patients develop AIDS?

Dr. John Mellors of the University of Pittsburgh Medical Center thinks he knows some of the answers.

Mellors has done viral-load assays on 1,604 gay men, 600 of whom were uninfected controls and the remainder in various stages of HIV disease.

He says he found an absolute correlation between disease state and viral load. Men whose viral loads exceed 19,000 particles per blood droplet are six times more likely to have AIDS compared with those whose viral loads are less than 4,000. And those who have more than half a million viral particles per blood droplet are 13 times more likely to die within a year than are men with a count of less than 10,000.

When viral loads are combined with a patient's level of CD4 cells - vital components of the immune system - the results are "diagnostic tools that rival anything we have in medicine today," Mellors says. "The speed of the train is the viral load, and the time to the [AIDS] disaster is indicated by the number of CD4 cells."

So, Mellors tells fellowphysicians to do viral-load and CD4 tests. Then to put patients on the combination of the physician's choice. Two weeks later, "if therapy is having an effect, you should see it," Mellors says, in the form of a sharp drop in viral load. And, "the maximum effect should be hit by six months," he says.

The viral-load level at the six-month point is what Mellors calls the "set point" for HIV - the amount of virus that is effectively controlled by the drugs. Every three to four months, says Mellors, doctors should retest their patients to see if the viral load has risen appreciably above that set point. If it has, he says, switch the patient to a new drug combination.

Much of what Mellors says has been verified in other laboratories. The clear relationship between viral load and stage of illness seems to bear up, as does the notion of a set point.

But there are troubling, inexplicable exceptions and mysteries. For example, Dr. Doug Mayers of the Walter Reed Army Institute of Research says there are "reports of people getting undetectable [viral] levels and still dying."

How could that be?

One possibility is that the patients' immune systems are so thoroughly devastated by years of HIV infection that even minute amounts of virus - a few hundred thousand particles - can cause a fatal illness. If that's so, some scientists say treatment ought to begin early, before the immune system has been wiped out.

But doctors worry that starting patients on complicated life-long drug therapies before they've developed AIDS could leave them with no effective treatment options later, when they get sick. Why? Because of drug resistance.

In general terms, scientists know that HIV mutation and the appearance of drug-resistant strains of viruses are a function of classic evolution. Put pressure (in the form of drugs) on a species (HIV) and it will evolve around that pressure. The only time HIV can mutate is when it reproduces - and as it makes copies of itself HIV is sloppy.

Mutations are common: For each bit of HIV genetic information (or nucleoside), the odds are one in a thousand that a replication will produce an error. If humans mutated at that rate, our species would be a mess - we probably would not have survived. But for HIV, such a rapid mutation rate is key to its survival and ability to outwit the ever-vigilant human immune system.

"What this means," says Dr. Douglas Richman of the University of California in San Diego, "is without replication, you can't get HIV resistance. If drug therapy knocks viral loads down to below detectable levels, you're not getting replication, and there's evolutionary arrest, so far as we can tell."

It also implies, Richman says, that if a doctor is going to treat an HIV patient at all, it should be early in the disease state, using the most powerful possible combination of drugs. Using weaker drug regimens (such as AZT alone or AZT plus d4T, for example) is, he says, "a genetic misadventure" that will allow enough continued HIV replication to permit viral mutation and evolution.

The Merck pharmaceutical company's top HIV scientist, Dr. Emilio Emini, agrees. He says that "HIV is genetically unforgiving," and "resistant virus selection can only be prevented by imposing a fully suppressive antiviral therapy."

Emini says that full suppression of HIV is achieved by two aspects of drug therapy: its anti-HIV potency and the drug's "genetic barriers."

Even potent drugs are quickly rendered useless if HIV has to mutate only two or three places in its genes to become completely resistant. But if overcoming a particular combination of three drugs requires HIV to undergo more than a dozen mutations, Emini argues, the virus will be "unable to overcome the genetic barrier."

Dr. Scott Eastman of the Chiron biotechnology company in California has developed sophisticated technologies for monitoring HIV mutations. He says that once a resistant mutation emerges and the virus "starts replicating, the process is over in a matter of weeks." Mutant viruses in patients double their population, he says, every 1.3 days.

In theory, doctors can deal with that. If a patient's viral load starts to climb, the physician can simply put the individual on a new set of drugs.

But in practice, things are still more complicated.

When HIV manages to mutate effectively against one drug, that evolutionary leap often gives the virus the ability to withstand other chemically related drugs. This is called cross resistance. And if enough cross resistance is induced, there may not be a secondor third-string drug combination to which patients can be switched.

Dr. Ronald Swanstrom of the University of North Carolina has discovered significant cross resistance to more than one protease inhibitor. Up to 75 percent of the various mutations HIV makes to outwit one of the protease inhibitors will hand down resistance to another protease inhibitor.

Even worse, cross resistance is seen in the case of nucleoside analogs.

British researcher Noel Roberts of Roche Products Ltd. in Hertforshire believes, "We have provided a good armory of compounds for physicians to use in the treatment of AIDs."

BUT HE has found plenty of cross-resistant viruses in patients taking protease inhibitors. The smallest amount of cross resistance, he says, is induced by the drug saquinavir. Viruses resistant to ritonavir readily become cross-resistant to indinavir and the still-experimental protease inhibitor nelfinavir. And HIV resistant to indinavir acquires a broad cross resistance to all the other protease inhibitors.

When Roberts presented this data at a recent NIH meeting in Washington, D.C., New York AIDS activist Spencer Cox - who was in attendance - audibly gasped and said, "Well, that's it for me."

A founding member of the Manhattan-based Treatment Action Group, Cox has attended most of the key scientific meetings on HIV during the past decade. He's even been appointed to various NIH advisory committees, including one that is trying to decide how doctors should use these drugs.

Over the years, Cox has taken whatever drug the AIDS scientists were most strongly recommending at the time. And as the viruses in his body developed resistance or the toxicity of each drug proved unbearable, Cox switched therapies.

Recently, Cox stopped taking ritonavir (in combination with d4T and 3TC) because that protease inhibitor had side effects so severe that the 31-year-old Manhattanite felt as if he were suffering a permanent case of the worst flu imaginable. At the end of the summer Cox switched to indinavir.

Laboratory data indicate that Cox' current regimen may not be working, even though he has complied with all doctor's orders over the years and carefully adhered to his medication regimens. His viral load is 115,000 particles per droplet of blood, or about 575 million viruses in his body. And his CD4 count hangs at 250, precipitously close to the 200 level that meets the Centers for Disease Control definition of AIDS.

"When I saw Noel Roberts' data I thought, `Oh great, now I'm probably resistant to everything.' But I make no assumptions. The worst-case scenario is that I effectively am back in 1987: I've got multidrug-resistant HIV, and my therapies are moderately effective."

In contrast, fellow TAG member Mark Harrington attended most of the same scientific meetings over the years and made a different choice: take nothing. Until this summer, Harrington looked at the data on each of, as he puts it, "the drug du jours" and decided none looked good enough. When AZT monotherapy was in vogue, Harrington said no. When AZT / ddI dual therapy was hot, Harrington still said no. And he kept rejecting the options until this year.

Since August, Harrington has been taking the same triple-combination cocktail as Cox, but with markedly different results. In just four months, his viral load has gone from 200,000 particles per droplet to undetectable levels. And his CD4 count has doubled from 159 to 320. He feels terrific.

"I think both Mark and I agree that how we ended up in our respective positions was entirely accidental," Cox says. "None of us would say that having access to the best available scientific information every step of the way has helped us particularly. Professional judgment has consistently been way out in front of evidence."

At a recent meeting on development of new standards of care for HIV, Cox listened to Mellors' confident rendition of an appropriate recipe for treatment. And then the young activist exploded.

"When 3TC came out," Cox said, pointing to Mellors and other scientists in the room, "you and you and you all said the results were stunning. And you told us all to go on 3TC plus AZT. That was last year. And now it turns out that 3TC promotes cross resistance. And now our options are severely limited because of resistance. We suffer terribly from hubris!"

The Rockefeller Foundation's point man on AIDS, Seth Berkley, stands back and analyzes the situation, then concludes, "We're going to need many more generations of drugs because of resistance, and they're going to get ever more expensive."

At some point, Berkley says, America has to recognize that this entire approach isn't cost-effective.

Assuming, conservatively, that 250,000 Americans, or a quarter of the current estimated HIV-positive population, take combination-drug therapy for an average of 35 years each, at an annual cost of $25,000 for drugs and associated tests, by 2031, the American tally would theoretically be $218 billion.

Becoming Resistant / How HIV can become resistant to drugs:

1. Without drug treatment, about 100 billion HIV are made daily in an infected person's body.

2. Treatment with a combination of three drugs reduces HIV production to the point where very few viruses can be found in a person's body.

3. But if the treatment is not potent enough, or if a person fails to take the drugs regularly, HIV quickly reproduces and swarms back into the bloodstream.

4. HIV is very sloppy. When it makes copies of its genes, the virus makes many mistakes, producing thousands of mutant HIV every day.

5. If such random mutations help make the virus resistant to a person's drugs, the mutant population will quickly grow and soon outnumber normal HIV cells.

6. Changing drugs also may lead to the production of mutants that have made more than 10-15 such advantageous errors in replication and may be able to resist all available treatments.
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Always watch for outdated information. This article first appeared in 1996. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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