Follow PI doses or don’t prescribe them at all, researchers say

States setting compliance criteria for protease inhibitors

Compliance is so critical to keeping HIV under control that AIDS experts are urging physicians to discontinue therapy rather than reduce dosing because of side effects. And in several states, AIDS drug assistance programs (ADAPs) are requiring proof of previous drug compliance before dispensing protease inhibitors to patients.

"Drug resistance is the No. 1 problem we face in dealing with HIV infection," says John Coffin, PhD, professor of medicine at Tufts School of Medicine in Boston. "The number of mutations HIV must go through to overcome the suppressing effects of the drug is directly dependent on the doses of the drugs."

Speaking at the recent annual conference of the American Association for the Advancement of Science in Seattle, Coffin presented some of the issues that are facing the National Institutes of Health advisory committee in setting new guidelines for antiretroviral therapy. The two biggest issues it has confronted are when to initiate therapy, and with what regimen — decisions that have a direct impact on compliance.

A member of the committee, Coffin says compliance is a more crucial issue than researchers expected when developing the drugs. They had hoped the drug would fit so tightly into the protease enzyme’s structure that its action would be completely blocked. The enzyme, however, has proven to be flexible and resistance does develop, albeit more slowly than with earlier drugs.

Virus must mutate six times

"The earlier drugs required only one or two mutations of the virus for it to become drug-resistant," Coffin says. "The protease inhibitors work because the virus needs to mutate six or more times with the proper dose" before resistance develops. If the dosage is followed correctly, it may take years before a viable mutation evolves, he adds.

Compliance is so difficult with combination therapy that it has become an important factor in deciding how and when to start therapy, Coggins tells AIDS Alert.

"Compliance was one of the points of discussion [among the panel] about when you start treatment," he says. "It is a reason for considering delaying treatment in people who are not at great risk for immediate progression."

The panel itself did not specifically discuss how to improve compliance, but Coggins says he opposes one school of thought that suggests patients stagger their treatment rather than taking a combination of three or four drugs at a time.

"I and other people who think about that theory were very concerned about the idea of staggering the start of drugs," he says.

Starting with 3TC alone, for example, is not wise because resistance can begin within two weeks. "My thinking would be that it is much better to start [drugs] all at once if possible."

Indeed, the National Institute of Allergy and Infectious Disease recently stopped clinical trial ACTG 320 after interim results showed significant clinical benefits in patients taking three drugs rather than two. (See trial results on p. 39.)

Deciding when to start remains difficult because patients have not been treated long enough to know whether sustained treatment can eradicate the virus completely or keep HIV disease at bay indefinitely, Coggins says. "If there was the probability of eradication, then of course you start everyone right away. But if there isn’t, then I think it is a very tough question. Do you subject someone to drugs for ten years, and perhaps strongly risk getting the development of resistance virus at a time when you might have been much better off waiting?"

Anthony Braswell, RN, MPH, director of AID Atlanta, knows of clients who have been on protease inhibitors for less than two months before they become frustrated by the demanding regimen or the debilitating side effects. "They get tired of the regimen and then they start getting lax on their medication," he says. "Everybody is sitting on the edge of their seat because we are going to get a supervirus out there that is resistant to everything."

The concern over resistance is so great that states are using compliance as a criterion for dispensing the drugs. Ryan White CARE Act legislation gives states control over setting eligibility requirements for ADAPs, which use Ryan White funding to provide AIDS drugs for more than 100,000 low-income patients, about half of whom are believed to be on triple combination therapy. Faced with overwhelming demand and limited funding for expensive drugs, at least three state ADAPs — Georgia, Louisiana, and South Carolina — have written guidelines that allow providers to refuse to prescribe protease inhibitors for patients who do not have a good record of compliance with other drugs.

In Georgia, for example, a patient must be provider-certified as compliant both in taking previous therapy and in getting to appointments before they are prescribed protease inhibitors, Braswell says.

Building compliance into treatment

"Until now, people could say, ‘Give me my drugs. I’m a taxpayer.’ And you didn’t have any say," he says. "This is the first big step in building compliance into it and giving the provider the power to say, ‘No, you can’t even take your AZT right. I’m not going to put you on protease.’"

Louisiana’s medical eligibility criteria state that an "applicant must demonstrate compliance with medical treatment, clinical appointments, and laboratory work." It goes a step further than Georgia by also requiring that patients test for viral load before entering the program and at least every six months in order to be recertified.

Until now, compliance has not surfaced as an issue in determining eligibility. Although the development of resistance has always been an issue in antiretroviral therapy, the fact that protease inhibitors are so costly (more than $10,000 annually for triple therapy) and popular has forced ADAPs to wrestle with a whole new set of eligibility requirements. Because the issues are so controversial, many ADAPs have included ethicists and AIDS patients on their advisory panels, says Arnie Doyle, a research associate specializing in ADAP issues for the National Alliance of State and Territorial AIDS Directors in Washington, DC.

Don’t throw money away

"If you are providing a real expensive drug and trying to serve as many clients as possible, you want to make sure those people you are serving are utilizing the drug appropriately and not throwing money away," Doyle explains.

So far, the regulations are so new that most people aren’t aware of them or haven’t thought out their implications, says Bill Arnold co-chair of the ADAP Working Group, a Washington, DC-based coalition of pharmaceutical companies and AIDS organizations.

"I think it will be extremely controversial once people start to think about it, because what is the alternative? If you aren’t going to give them protease inhibitors, what are you going to give them? AZT? Malpractice. A dual combination? Close to malpractice. So if you are not giving somebody access to protease you need to be prepared to defend — if you want to drag the argument out a little bit — that you could be sentencing them to an early death."

Kenneth Mayer, MD, director of the Brown University AIDS program in Providence, RI, agrees. "It is a real concern," he says. "Certainly we don’t want to have treatment apartheid based on demographic characteristics that say this person is likely to be noncompliant. I think you have to individualize it."

While compliance criteria appear to be unprecedented in AIDS care, legal experts say they are unaware of state laws that prevent programs from making compliance restrictions. "I don’t know of anything that says legally they can’t limit a beneficial drug," says Matt Coles, director of the AIDS Project for the American Civil Liberties Union in New York City.

There are other drugs, such as steroids or antibiotics, that cause resistance if not taken properly. Restrictions are not considered for those drugs, however, because they are much cheaper and the consequences of resistance are less catastrophic, Coles says.

"I think it would be very difficult to challenge legally because they are just going to say, ‘Look, the drugs are no good if they are not taken regularly, and in fact they may be bad. So we don’t have an obligation to buy drugs for people when they are not going to be used correctly.’"

Doyle notes, however, that not enough is known about the short-term benefits of protease inhibitors and that a limited time on the drugs may provide clinical benefit. Another point raised by some AIDS experts is that patients may have more incentive to comply with protease inhibitors because, unlike previous antiretrovirals, they have such a remarkable, measurable benefit.

ADAP clients lack clout

It is unlikely that the restrictions will be challenged because most ADAP patients are poor, homeless, or injection drug users, says James Arvantes, editor of the ADAP Report, a newsletter funded by Glaxo Wellcome Co. of Research Triangle Park, NC. "The people who won’t be compliant wouldn’t have the clout to take them to court," he says.

How well compliance criteria will be enforced is difficult to judge, says Doyle. Louisiana’s viral load requirement ostensibly would allow officials a measurable indicator of whether a patient is on the drugs. But, as Doyle points out, there may be other factors than compliance attributable to improvements in viral load. Most likely, he says, states will leave the compliance issue for the provider and patient to work out rather than closely monitoring patients themselves.

With increasing evidence that therapy works best when using three-drug combinations, Doyle says states will face even heavier demands for protease inhibitors.

"I think this is only the tip of the iceberg," he says. "With ACTG 320, it is pretty clear that triple combination is the way to go. If it becomes the standard of care, then it will put an increasing burden on the programs."