The Bay Area Reporter - July 2, 1999
Matt Sharp, ACT UP/Golden Gate Writers Pool

The good news is that the anti-viral "cocktails" have helped most people with HIV to live longer. And not just longer, but better: we are seeing less illness, fewer hospitalizations, and more people returning to work and school who once thought they'd be six feet under by now.

The bad news is that the cocktails have raised a cloud of discomfort, unease, and confusion because of side effects and drug interactions. Many times the patient's health is jeopardized by the taking of so many drugs, and the situation may only be getting more complicated and confusing as more drugs become available.

CYP450

Most anti-viral drugs are processed by the liver where they are broken down (metabolized) to be absorbed into the bloodstream. Enzymes are the chemicals that break down the drugs in the liver. Sometimes anti-HIV drugs can interfere in one way or another with this enzymatic process, called the CYP450 system. Here lies the problem with combining all of the therapies used today. With so many drugs that compete with, inhibit, or induce this CYP450 process, dangerous interactions can take place, possibly causing serious problems.

(It should also be noted there are also possible benefits to drugs being used together. Drugs that potentiate each other in combinations are called synergistic. In other words, using some drugs together may make them even a more powerful weapon.)

Pharmacokinetic (PK) studies look at how a drug is broken down, ascertain how it will be absorbed in the bloodstream, and determine what drugs will compete for and interact with each other. Drug companies often skip over these studies because they are expensive, a hassle, and not required for licensing. If tests are completed, however, the company can then go on to warn patients what to avoid while on the particular drug, through package inserts. But there are so many drugs being used the companies won't and can't perform all the necessary PK studies. The FDA only "asks" that they perform trials in drugs that are commonly combined. So, many combinations are missed.

Further complicating the problem is the fact that there are new drugs coming out all the time that have not been through the PK studies, and patients and doctors are haphazardly making the decision to use them in order to come up with an effective regimen for people with few options. A good example is the new non-nucleoside Sustiva that was found to lower levels of the new protease inhibitor Angenerase (amprenavir) in the blood by up to 40 percent, therefore causing less drug to get to the virus, possible causing drug resistance û a sad scenario given that these new drugs are given to people who probably have few therapy options. So, without the needed interaction information, poor choices for therapy are being made.

(New positive information has come forward that may remedy the detrimental Sustiva/Amprenavir combination. In a study by the National Institutes of Health, it was found that Ritonavir, an older protease inhibitor, used at 200 mg. twice daily, will restore the levels of Amprenavir used with Sustiva. Further efficacy data will be forthcoming to find out if this may be a good strategy for people with few available treatment options.)

Weigh the pros and cons

A further complication is that many drugs will never see the light of day in PK interaction studies. We may never know the interactions between anti-HIV agents and street drugs such as speed, heroin, ecstasy, and crack, drugs clearly being used today by some people with HIV. Its a systematic problem because the drugs are illegal and therefore samples to study are impossible to acquire. Plus, there is no quality control of street drugs. What may be studied in a laboratory might be completely different than what is bought from a street dealer.

Ben Cheng, information and advocacy associate at Project Inform, sees at least a partial solution. "The companies should be doing 'nested' PK studies in all the new trials, in order to look for drug interactions." These are trials that happen at the same time as regular approval trials that would gather data on drug to drug interactions while the drugs are in their development track. Of course this won't give us many answers for other, older combinations or street drugs, but it is certainly a possible starting point.

Even if studies have been done on interactions, the most informed patients and doctors may miss the warnings. The FDA has set starting goals that 50 percent of all new drugs must be required to use patient inserts to warn of dangerous interactions. Congress passed legislation that required 10 drugs a year to include patient inserts, clearly an inadequate number given the number of possible combinations available today in AIDS treatment.

"The main thing is just to be cautious and not make hasty decisions," said Dr. Steven Deeks, AIDS researcher at San Francisco General Hospital. "As physicians we have the responsibility to more often than not have time to weigh the pros and cons of treatment choices so as not to harm our patients."
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Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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