Protease Inhibitors: Major Study Stopped When 3-Drug Arm Proves Superior

ACTG 320, a controversial clinical trial conducted in 1,156 volunteers at 41 U.S. medical centers, was stopped early after the combination of indinavir (Crixivan(R))+AZT+3TC proved superior to AZT+3TC alone. There were 8 deaths in the triple-combination arm, vs. 18 in the double combination.Total cases of disease progression (AIDS-defining illness ordeath) were 63 in the AZT+3TC arm, vs. 33 with the triple combination.

Participants in this study had CD4 counts below 200 (with amedian of 86). All had taken AZT for at least three months, but had taken no more than one week of 3TC, and no protease inhibitors.

Participants will now be offered various options, including rollover studies which may include experimental drugs DMP-266 and 1592 which otherwise are not widely available. Complete details are not available at this time. It will be important for participants to be well informed so that they can best choose among the options available to them.

It is widely agreed that what is important about the treatments tested in this study was not the number of drugs,but the use of a combination powerful enough to reduce the viral load to undetectable levels. The viral load data are being analyzed now.

The Controversy

Strongly supporting this trial was the Treatment Action Group(TAG) in New York, which released a 3,000-word backgrounder,with a detailed table of the results, on February 24, the same day of the NIH announcement that the trial had been stopped. (The backgrounder is available through the TAG homepage, http://www.aidsinfonyc.org/tag/) TAG Policy Director Mark Harrington stated, in a February 24 press release:

"This study will probably mean that tens of thousands more people will live longer, healthier lives than would otherwise have been the case. Historically we've seen that well-designed controlled clinical trials are the most effective way to change treatment patterns for most people with AIDS.ACTG 320, along with other recent research findings, should convince skeptical insurers, physicians and patients thatthese potent combinations of anti-HIV therapies are safe,effective, and cost-efficient for the treatment of advanced HIV disease. That, in turn, should substantially increase patients' access to the drugs."

Other activists, while strongly agreeing with the push for improving the standard of care, have long been unhappy with the study, for a number of reasons:

* We already know that more viral suppression is better than less suppression. The main result of this trial was to prove that yet again.

* One of the most important questions now is the long-termtoxicity of the protease inhibitors and other antiretroviral drugs available. ACTG 320 does not help with that question,because it followed patients for up to a year (median 38 weeks).

* ACTG 320 also does not help answer the question of when to start therapy. Only participants with CD4 count under 200 were enrolled in this trial, and the results were driven by those with CD4 counts under 50.

* There are also concerns about the opportunity cost of using government resources for product-oriented trials which should be industry's responsibility, instead of using those resources for critical research questions which industry has little incentive to address.

* Another issue is the enrollment of persons (often minorities) in suboptimal trials because they do not have better treatment options.

We believe that it is long past time to stop reaching reflexively for "clinical endpoints" (death or serious disease progression) just because we are not quite ready to trust viral load. In theory, clinical-endpoint trials of a particular treatment combination could tell us whether the benefit of viral load reduction outweighs any long-term toxicity of the regimen (over the next five, 10, or 20 years). But in practice, long-term trials are not feasible when treatment is changing as rapidly and unpredictably asAIDS treatment is today. What, then, is the rationale for trials like ACTG 320?

Or will we be forced to move now to a two-track rationale --one for experts and patients with means, and another for insurance companies, government agencies, and non-expert physicians, who need body counts to persuade them to change to a modern standard of care?