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Being Alive
The Message From Vancouver: The Hope is Real and the (Reality) Check is in the Mail
Walt Senterfitt
August 5, 1996
Being Alive 1996 Aug 5: 7

Most readers have heard a lot by now about the XIth International Conference on AIDS in Vancouver and most have probably been affected by the strong message of new hope that was conveyed by the mass media and returning delegates. Many have also raised skeptical eyebrows, along with questions like: "We've heard all this excitement several times before, with AZT, then ddI, then AZT+3TC. Is it really different this time?" "Completely suppressing HIV may be possible for those with brand new infections, but what about those with already-advanced disease?" "How many of us are going to be able to afford all these new treatments and tests?" In my view, the hope is very well foundedxand so are the doubts and questions. Here's a summary of what I see are the five major reasons for new hope and the five major cautions.

Five Good Reasons To Be Hopeful 1. We have a number of effective new antiviral drugs to use as elements of combination therapy: indinavir (Crixivan), ritonavir (Norvir), saquinavir (Invirase), and nevirapine (Viracept) approved in the past six months. Several more protease inhibitors and other antivirals are near the end of the pipeline, some of which look at least as promising as those on this list. Furthermore, we don't have to rely on a few small studies with highly selected populations for our optimism. Reports at the conference gave us encouraging data from dozens of trials of various combinations of these and older drugs. It's also easier to take the hopeful data for good coin, when many of us have seen ourselves or friends doing dramatically better with the new combinations. (Nearly 30,000 PWAs in the US have begun taking Crixivan, usually in combinations, since it became available.) 2. We have a powerful new technology-viral load or PCR testing-which permits rapid evaluation of the effect of drug therapy on the amount of virus in the bloodstream. This helps scientists and clinicians rapidly decide whether a new candidate drug is promising or not, and helps individuals and their providers make decisions on individual treatment regimens. Viral load testing is also turning out to be a significantly better predictor of the future course of one's HIV infection than T-cell counts. Viral load (in the absence of treatment, that is) is less variable over time in a person than we had thought. After only a few months of infection, an individual is now thought to reach a "steady state" of viral replication, indicated by a person's typical viral load or "setpoint." (The setpoint is analogous perhaps to one's normal or typical body weight.) Dr. John Mellors of the University of Pittsburgh presented an update of his analysis of the MACS (Multicenter AIDS Cohort Study in gay men) data showing that, on average, this setpoint predicts very well how soon or late a person will develop AIDS. This predictive ability of viral load measurement can also help guide individual treatment choices: in general, the higher it is, the more aggressive you will probably want to be in treatment.

Let me step aside for a moment to a frequently asked question: Does the fact that viral load is a better predictor of prognosis and drug effectiveness mean that CD4 counts are no longer useful? The answer is no. An elegant illustration was provided in a Conference plenary by Tufts University researcher Dr. John Coffin. He put up a slide of a locomotive traveling down railroad tracks toward a canyon where the tracks had been washed out and the train would surely crash. The canyon represents the crash or collapse of the immune system, i.e. full-blown AIDS or death. Coffin said we can think of CD4 numbers as the mileposts along the track that tell us how near or far our bodies are from the point of immune system crash, whereas the viral load numbers are like the speedometer readings that tell us how fast we are approaching the crash point. In theory (with a lot of evidence accumulating to support it), if we can stop viral replication entirely, then the train stops and gets no closer to immune collapse. To stretch Coffin's metaphor a bit, the hope is also that stopping the locomotive will give us the time necessary to learn how to rebuild the bridge over the canyon and avoid crashing at all-that is, to reconstitute or at least effectively prop up the damaged immune system.

3. Development of resistance to antiviral drugs can be greatly slowed, and possibly suspended entirely, if viral load can be kept very low, preferably near zero. Several studies provided evidence for this proposition, and others provided hopeful evidence for how some combination regimens work synergistically to counterbalance viral mutations resistant to one but not all of the drugs in the combination "cocktail." Key questions in the area of resistance remain unanswered, however, such as what to do about resistant strains already existing before viral load is reduced, as well as resistant strains transmitted to newly infected persons. And of course we need to know a lot more about the resistance patterns and cross-resistance patterns of the protease inhibitors, especially when conditions arise that mean we must interrupt the regular schedule of taking them.

By the way, it is important to note that the viral load tests currently available cannot measure levels below about 500 copies (of HIV RNA) per ml of blood plasma, which is definitely not zero. If one's viral load test comes back "undetectable," it could mean 499 copies/ml or it could mean a true zero. In reading reports, pay attention to whether the researchers have used the standard tests or the new third generation PCR tests which can measure viral loads as low as 25.

4. The effectiveness of the new antiviral combinations is both more profound and more durable than anything we've seen before. Even in relatively late-stage infection and with long histories of treatment with earlier antiviral drugs, as with the Merck clinical trial of Crixivan where the starting average CD4 count was 142 and the average viral load more than 40,000 copies/ml, more than 80% of the participants who could tolerate the drugs have undetectable viral loads after a year and sustained rises in CD4 counts of more than 100 T-cells. In earlier stages, the results are even more impressive. Mind you, only a few people have been treated this long so far, and we therefore most definitely don't know how long this level of viral suppression will last, but it's already far better than anything achieved with AZT or ddI monotherapy and clearly better than the best two-drug combinations like AZT/3TC or ddI/d4T.

5. Scientists have even more hopeful developments in the works. Newer, "designer" drugs have shown exciting results in early clinical trials. Some of them have attractive characteristics like better absorption and thus greater "bioavailability" (the percentage of a drug taken that actually makes it into the bloodstream in usable form). Some can be taken less often or with less dietary restriction. Some show more favorable resistance patterns. Some will attack yet another, different part of the HIV life cycle, meaning that combination therapy will be less vulnerable to the development of resistance.

Technology for testing the drug-resistant mutations and strains of virus in an individual's body is not that far from being widely available. Right now, this technology is limited to specialized research laboratories because it is so labor intensive and expensive, but breakthroughs permitting much higher volume and thus cheaper testing have occurred recently.

The basic scientists were also quite excited about the newly discovered proteins or "chemokines" which seem to either facilitate or prevent infection of immune system cells with HIV. These are also the same as or related to the long-sought (by UCSF's Dr. Jay Levy and others) CD8 cell factor or factors that seem to make certain people almost immune to HIV infection despite repeated high-risk exposures, and perhaps contribute to long-term non-progression by some infected people. Though the sessions about chemokines were mobbed, it didn't get much press-perhaps because researchers are still divided on the meaning of these new discoveries and their possible relevance to treatments or vaccines. Dr. Robert Gallo and some of his colleagues believe that chemokines can be the basis of both vaccines and new antiviral drugs that can be much cheaper, more natural and easier to take than anything now available.

Finally, a number of researchers have put forward a rational and testable hypothesis that HIV can be entirely eradicated from an infected person's body, if the infection is treated early enough, long enough and "hard" enough. This is where the "cure for AIDS" hype comes from. It is clearly way premature, perhaps irresponsible hype, to describe this hypothesis. (This deserves and will get a whole separate article next month.) And Now the Problems 1. We remain ignorant of much we need to know about how and when to use these new antiviral combinations. This ignorance results in disagreements among experts and confusion for PWAs and local doctors. For instance, the International AIDS Society convened a panel of experts last winter to come up with a new set of "state of the art" guidelines for when to start and change antiviral therapy and what to start with or change to. The recommendations were published in the July 12 issue of the Journal of the American Medical Association and distributed and explained at the conference. These experts recommended a much more aggressive approach to therapy, guided by both CD4 counts and viral load, than had been the basis of previous standard practice. But in at least one way, they were criticized as being too conservative and out of date: they recommend starting therapy with a two-drug combination of the nucleoside (AZT, ddI, 3TC, and the like) type and then changing to include a protease inhibitor once there's evidence of the above regimen starting to fail. Other experts argued that you should start therapy, whenever you do so, with the most potent regimen available. Go figure, for now, because no one actually knows the answer.

We also don't know whether and how these drugs may work somewhat differently in women. We don't know enough about interactions among these and other drugs. We don't know how best to manage side effects. We don't know enough about cross-resistance among protease inhibitors. And so on.

2. The prices of the new combos are very high and access to them is limited. Same for the costs of viral load tests and other monitoring needed to use them effectively. Who will pay? What will we as a PWA community, a medical care community and a body politic at large do about some people getting life-extending treatments and others being told, "sorry, no more life preservers: sink or swim on your own." And I'm just talking about this wealthy country for now, let alone the 90% of infected people who live in developing nations. As one commentator remarked, "If AIDS could be cured by one glass of clean water, the cure would be out of reach for a majority of the world's PWAs." For now, we have won victories that mean the federal/state AIDS Drug Assistance Program (ADAP) and Medicaid (MediCal in California) will include protease inhibitors and combination therapy regimens in their coverage. However, if long-term treatment at $16,000-$25,000 a year is adopted by large numbers of people currently in care as well as those we will encourage to discover their HIV positivity and seek treatment, it won't take long to break the bank. (I estimate the national annual cost of simply providing these drugs to half the currently non-treated HIV+ population as $8 billion a year.) What will be the effect of cost-cutting pressures in HMOs and managed care plans? Fewer and fewer HIV-infected people have private insurance coverage.

Some activists are demanding more government funding especially for anti-HIV drugs while others are demanding that the drug companies lower their prices. While both strategies may provide short-term benefit, neither one seems particularly realistic to me as a long-term guide to action. Capitalism demands maximum profits and PWAs compete with a host of other unmet health and social needs in a climate of right-wing political reaction. We clearly need a renewed AIDS activist movement, more leaders and rank and filers, and a lively discourse on strategy.

3. "Compliance" with the schedule for taking the protease inhibitors appears, at least for now, to be very important in preventing the multiplication of resistant virus. It is also very difficult, especially with the other restrictions about taking drug on an empty or full stomach and about preventing adverse drug interactions. Some are wisely recommending that a person should not begin combo drug treatment that includes a protease inhibitor until s/he has thought and talked it through and is ready to make the commitment to stick with it religiously.

4. We do not know how long the positive effects of the new drug therapies will last. For individuals, this implies that another good item to put on your checklist before beginning serious kick-ass therapy is a backup plan. Make your initial decisions in part on the basis of what you will do next if and when Plan A stops working or shows early signs of slippage.

5. Most, though not all, of the really dramatic and over-hyped studies-especially those about possible eradication of HIV replication-were in people who are the easiest to treat. This means people in the stage of primary infection (more or less the "window period" before one seroconverts to being HIV+) or very early in the period of asymptomatic infection and/or intermediate-stage but "drug naive" persons, meaning they'd never taken any antivirals before starting these potent combos and thus were likely to have fewer problems with resistance. The later one is in infection, the likelier one is to have intolerable side effects, the harder it is to completely suppress viral replication and the greater one's accumulation of resistant mutant strains of HIV. Furthermore, even when viral replication can be mostly or entirely arrested, one's immune system may be so damaged as to be unable to fight off all OIs, malignancies and other complications.

We still need, in other words, aggressive research efforts toward immune system reconstitution and other immune boosting therapies.

I find it hard to balance the hope and the caution; it seems natural to fall, perhaps alternately, toward one pole or the other. It is hard to make individual decisions which may have irreversible consequences on the basis of inadequate information. The Vancouver conference's motto "One World, One Hope" is clearly an aspiration, a noble one at that, rather than a reality. Yet, for at least a large chunk of US (and European and Australian and Japanese and other relatively wealthy) HIV+ persons, there is new hope-reflected not only in the tons of data but in the life stories being extended and animated every day. Some of us are cautiously peeking out of our bunkers, looking at the possible future in a new way, and whispering to each other, "D'ya think we might actually live long enough to get old?" As individuals facing choices only partially informed, we have little choice-we either roll the dice and decide to wait, or we make the best educated guesses we and our providers can come up with and hope the new monitoring tools will help us correct our flight paths early enough. As a community, or a collection of interwoven communities, and as individual actors in the lives of these communities, we do have a range of choices. It is my belief that the progress we've made to date is largely because of collective responses and collective action on behalf of ourselves and our larger communities. I dare to hope that we can renew that ethic and spirit of sharing.