VIRUSMYTH HOMEPAGE

HAS AIDS BEEN BEATEN?

By Colman Jones

Now On 2-8 Jan. 1997

Four months ago, Michael Steeler was a very sick man.  He and his doctor both thought the end was near.

"I had bargained on it," Steeler tells me. "I had geared my finances and everything else to dying within the year."

Before his AIDS diagnosis in 1990, Steeler had led a distinguished career as a banker, ship broker and publisher of trade magazines. After years of trying almost every experimental treatment that came along, he was losing weight fast and his body was overtaken by chronic diarrhea.

Then, in an eerie scenario now being replayed throughout North America and Europe, Steeler began taking one of the newly available pharmaceutical compounds recently licensed to fight HIV. His symptoms quickly disappeared and he began gaining weight, yet another tentative success story in what may prove to be the most dramatic treatment advance so far in this public health calamity.

Just when it was beginning to look like the struggle to come up with a useful AIDS treatment was going nowhere, a new sense of hope emerged. Although no one is quite prepared to trot out the "C" word just yet, all eyes are focused on this latest class of AIDS treatments, known as protease inhibitors.

Foggy science

But the science of how to use these new remedies is foggy. And there is a disturbing subtext - the consensus as to which drugs to take and, more importantly, when to take them is being developed under the watchful eye of an industry intent on marketing them to as many people as possible.  

This state of affairs has led to concerns about the reliability of the information - supplied mostly from drug company presentations - people are relying on to make critical treatment decisions.

In July, a panel of top AIDS researchers issued a series of recommendations in the Journal Of The American Medical Association (JAMA). They advised people with HIV to take these new, relatively untested therapies even if they're not sick but simply show a certain amount of the virus in their blood, opening the door to a much larger pharmaceutical market than just full-blown AIDS cases.  

The move may well be justified, but some are beginning to question the motives behind the recommendations, given the backgrounds of the 13 panelists.

In accordance with recently developed rules of disclosure, JAMA published an addendum listing the authors' ties to industry. All but one had received financial support from AIDS drug makers, it turns out. Two of the panelists actually own stock in companies producing anti-HIV compounds such as protease inhibitors, JAMA says.  

At medical meetings, the constant presence of pharmaceutical reps is causing unease for some participants, who worry about perceived - or real - conflicts of interest in a potential multibillion-dollar market.

Should those who stand to profit from this biotechnology bonanza be the same people who are entrusted to impartially review the scientific evidence and issue recommendations?

Such issues matter little to Steeler. For him and others with HIV, the motives of the drug researchers matter less than the drugs themselves and their potential to offer him and others like him a new lease on life.

***

The latest addition to the AIDS treatment arsenal, protease inhibitors are designed to attack HIV by blocking an enzyme said to be crucial to the virus' reproduction, thereby crippling its ability to make more copies of itself - at least in theory. Accordingly, using several antiviral treatments in combination offers more opportunities to attack the virus.

Preliminary results indicate that using one or more of these drugs, often in combination with older AIDS drugs, causes levels of HIV in the blood to shoot down dramatically and the number of infection-fighting white blood cells to rise. Some unpublished studies even hint that patients taking these new formulas may actually be living longer - a first in more than a decade of AIDS drug development.

HIV levels

Indeed, if their effect on HIV levels in the blood is any indication, the drugs deliver a whopping one-two punch. In one study of indinavir, marketed by Merck-Frost under the trade name Crixivan, more than a third of those taking the drug had virus levels either at or well below the detectable limits of the currently used tests. This measurement of viral load, as it's known, is overtaking the counting of immune system cells as the chief "surrogate marker" doctors use to tell whether an anti-HIV treatment is working.  

For some observers, however, decreases in viral load have to be placed in perspective. "All of the drugs - AZT, etcetera - lower viral load, even down to undetectable levels," says Billi Goldberg, a prominent community treatment activist from San Francisco who insists the latest therapies are worthless.

While there is genuine uncertainty over the exact significance of these viral load tests, improvements in the immune systems of people taking these drugs are held up as further evidence of their benefit. The main yardstick of immune function most experts have traditionally relied upon is the number of white blood cells, known as CD4 cells, per cubic millimetre of blood. (Healthy people generally have between 800 and 1,000 CD4s, whereas people with HIV are currently defined as having AIDS if they show fewer than 200.)  

In the indinavir study, patients on the drug showed an average increase of more than 100 CD4 cells after six months, in many cases a doubling of their count.  

As with blood virus levels, however, numbers of CD4 cells alone are not the be-all and end-all of immune well-being.  

This was perhaps most conclusively demonstrated by the British-French Concorde trial, the largest and longest of its kind, comparing HIV-positive people taking AZT earlier and later in infection. It found that those who began taking the drug early on consistently showed higher CD4 counts yet died just as quickly as those who waited until they got sick, clouding the precise relationship of CD4 counts to improved health.

Furthermore, despite increases in CD4 cells, their ability to fight infection is not necessarily improved. A group of Dutch researchers found that "Although treatment with a protease inhibitor resulted in the most persistent elevation of both CD4 and CD8 T-cell counts, T-cell functional improvement was of limited duration."

Ultimate test

The ultimate test of any AIDS therapy takes place in the clinical setting, where both doctors and patients are primarily interested in preventing illness and death. In this respect, the reports flooding in about health improvements are the kind doctors and patients could only dream of even as recently as a year ago.

Says Joseph Sonnabend, a long-time AIDS physician in New York, "This is the very first time in the history of this disease that I see people who come back a month later - and the month after that - and they're better than they were. You don't know what that feels like - it's just terrific."

As a result, word is spreading like wildfire about these new therapies, and patients are storming into doctors' offices demanding them. Maurice Genereux, a Toronto HIV primary care physician, says he's been deluged by requests for prescriptions in the last six months.

Interestingly, many AIDS doctors don't feel the same enthusiasm as their patients about protease inhibitors, according to a Hoffmann-La Roche survey of 409 participants in a recent protease inhibitor symposium. Some physicians interviewed for this article express a cautious optimism about the efficacy of the drugs and are waiting to see more information on their toxicity and impact on survival.

Philip Berger, chief of the department of family and community medicine at the Wellesley hospital, agrees it's too soon to tell what the impact of these therapies is going to be.

"Do they do something? Yes, they do. Have I seen spectacular recoveries on the drugs? Absolutely. In everybody? No. In some people? Yes, and it is absolutely amazing. How long is it going to last for? I don't know - that's all I can say."

Sonnabend is quick to caution that "The protease inhibitors are not performing as their strongest adherents would have you believe. The clinical benefits have only been demonstrated in people who are rather sick. Most people don't benefit, because it doesn't work or they can't tolerate it, and in the people for whom it works, it stops working for a while."

Current uncertainty

At the core of the current uncertainty over the new compounds is the fact that no one knows exactly how best to administer them, or to whom.

"Even if the promise of some of the combinations that we're seeing lasts for a long time, there are still a lot of people for whom that's not the answer, whose access to these treatments may be difficult or whose immune systems have already suffered too much damage," adds Glen Brown, director of programs and services at the Canadian AIDS Treatment Information Exchange (CATIE).

There's also the question of side effects and interactions with the other medications patients may be taking. Of particular concern is ritonavir, one of the most highly touted of the new products.  

"There are a whole slew of other drugs that you can't take with ritonavir," notes CATIE treatment service coordinator Craig McClure, "because of the way the drug is metabolized in the body."

In fact, 17 per cent of the volunteers in a ritonavir trial conducted by the manufacturer, Abbott Laboratories, had to give up treatment because of adverse side effects.

As a result, AIDS treatment activists are hesitant to overly laud these latest treatments.

"Protease inhibitors are perhaps the beginning of the search for an end," says McClure, "in the sense that they are helping people to live longer and healthier, but they're not in any way, shape or form a cure."

Amidst all this contradictory information, people living with HIV are left with few places to turn for accurate, unbiased information about their treatment options.  

One school of thought holds that treatment should be started as early as possible to prevent damage to the immune system.  

"These drugs should be available to everyone no matter what the CD4 count is, early on if they choose," Genereux says. "I don't think there should be limits - set by anyone - on who has access to the treatments."

Others, like New York's Sonnabend, are more cautious, warning that not enough is known about the long-term effects of protease inhibitors.

"They're doing the same thing as with AZT," Sonnabend points out. "People who are not sick - asymptomatic people - are being placed on these drugs, with no evidence whatsoever that they're going to be helped by them. And those people may actually be hurt because of long-term toxicity."

The uncertainty as to when to begin treatment is reflected in the differing criteria being issued, on the one hand, by researchers and, on the other, by provincial governments - who have to pay for these latest additions to the AIDS treatment arsenal.

For example, it was recommended at the Vancouver AIDS conference that anyone with a viral load higher than 5,000 copies per millilitre of blood should be taking anti-HIV drugs, regardless of their CD4 cell count. Yet in Ontario, the new treatments are only available to people already taking anti-HIV therapy who have fewer than 500 CD4 cells, whether or not they have a high viral load.

Pricey drugs

Exactly who should have access to the protease inhibitors is no trivial matter to a province concerned with cutting costs. The new drugs are pricey - a months' supply of Saquinavir alone runs at $550.  

While debate continues over when to begin prescribing the new drugs, the definitive answer on whether they really stall AIDS can only be found by conducting properly controlled clinical trials.

But there's a catch-22 here. Because new anti-HIV preparations are continually being unveiled, organizing such trials is problematic owing to the reluctance of patients to keep taking an "old" drug. Furthermore, because of all the different concoctions of drugs being experimented with, trial designers face a unique challenge in trying to allow participants a certain degree of autonomy while still being able to achieve a meaningful scientific result.

What little evidence there is about an actual clinical benefit from these new treatments has mostly taken the form of interim reports presented by drug companies at medical conferences, not papers published in the peer-reviewed scientific literature.  

Some are suspicious of this kind of preliminary information, pointing out that it was the same sort of unpublished data that led to the 1990 licensing of AZT for HIV-positive people without symptoms, a move that later trials like Concorde cast resounding doubts on.  

In fact, that trial - the longest and largest of its kind - showed that more people taking the drug early on died than those who waited until illness struck.

Key studies

Oddly enough, when the JAMA panelists reviewed AZT studies as part of the July recommendations, neither the Concorde trial nor another critical study from the U.S. Veterans Affairs Administration was even cited, leading some to wonder how impartial these drug company-funded reviewers really are.

The omission of two key studies critical of early AZT use was pointed out in a September report published in JAMA, penned by Berger, that drew attention to the considerable ties between the panelists and industry.

Berger's concern about the increasingly blurry relationships between leading researchers and AIDS drug manufacturers was highlighted at a conference held last October in Toronto by the HIV Trials Network.

Funded by eight different AIDS pharmaceutical firms, it was convened to develop prescription guidelines for AIDS treatment. Drug company sponsorship of such events isn't that unusual, but some in attendance were struck by the constant presence of company marketing reps, even in the small group discussions hashing out recommendations on how and when to prescribe the drugs - recommendations that will form the basis for HIV treatment in Canada for years to come.  

(Final recommendations on when treatment with these drugs should begin are expected to be announced in the next couple of months.)  

Brown, who attended the October conference, doesn't know whether or not the guidelines were influenced by pharmaceutical reps in the room. "I'm not entirely sure, but I feel fairly confident that the conversation would have been just the same if they weren't in the room."

But untangling the complex web of ties between drug companies, researchers and activists is no easy task, given all the interdependent relationships that have developed in the course of the epidemic.  

"If companies stop funding HIV research, then you'd never have to worry about conflict of interest," says Pat Hanrahan, a spokesperson for Hoffmann-LaRoche, maker of Saquinavir. "But you'd also never have to worry about drug therapy, either," since drug companies provide the bulk of research funding.

Don Zarowny of the Canadian HIV Trials Network, who organized the October conference, agrees. "If we throw away all the researchers who receive funding from the private sector, we'd have nobody left." He says declining government funds means there's no choice but to have the pharmaceutical industry finance such meetings.

Zarowny rejects notions that discussions about prescribing recommendations were influenced by the presence of drug company representatives at the conference.  

Perceived threat

"We aired this in a small group prior to the meeting, and the bottom line was that there was no perceived threat from the presence of these people. It would be very difficult to promote a drug that was ineffective or extremely toxic."

Drug company hype is the last thing on Genereux's mind. "These drugs market themselves. The results are so impressive that the clinicians are trying to get these drugs before they're available."

But not all AIDS activists are impressed by this latest twist in the search for AIDS treatments. Perhaps most radical in outlook is the San Francisco chapter of the AIDS Coalition to Unleash Power (ACT UP), which has clearly distanced itself from the other ACT UP groups with its ringing denunciation of the antiviral approach to AIDS.  

"AIDS research money is all being dumped onto the study of these entirely worthless, highly toxic and extremely profitable pharmaceutical treatments," says Todd Swindell, a spokesperson for the group. "Things that will boost the immune system and alleviate the opportunistic infections - those areas are not being looked at."

To most workers in the AIDS field, this small group of radical guerrilla activists is merely taking advantage of paranoia fed by the disastrous results of AZT. Brown calls them "sociopaths," at least those he met in Vancouver.  

Ultimately, the bottom line is the day-to-day health of people with AIDS, like Steeler, whose seeming recovery is hard to argue with. Like many people with AIDS, he is trying to come to grips with the prospect of a life he thought he was leaving behind. Many of his friends are dead, and he has no idea whether the benefits he's experienced will last indefinitely or wear off.  

"I am hoping, of course, to stay around long enough to find something else that will help keep me going, until something else proves more effective," Steeler says. "Earlier this year, I had made my mind up that I would be dead within a year, so every day is a new gift."  

VIRUSMYTH HOMEPAGE