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D4T: New Clinical Data Confirms Benefit




 

AIDS TREATMENT NEWS #222, May 5, 1995

A major study of d4T (generic name stavudine, brand name Zerit) has shown that patients who have been using AZT did significantly better in disease progression if they switched to d4T than if they stayed on AZT. This new information is important for making treatment decisions; it confirms the decision to grant accelerated approval to d4T last year. Also, it shows that improvement in blood tests, including CD4 count and viral load in peripheral blood cells, can predict later clinical benefit to patients.

The new information, from the '019' study sponsored by Bristol-Myers Squibb, was presented at the Eighth International Conference on Antiviral Research, April 23-28, in Santa Fe, New Mexico. This study included 822 patients, with CD4 (T-helper) counts between 50 and 500. All had taken AZT for at least six months, but many had been taking it much longer than that. Ten percent of the patients had a diagnosis of AIDS at entry.

These 822 patients were randomly assigned to either continue using AZT, or to switch to d4T; neither the patients nor their physicians knew who was getting which drug. Patients were on the study for at least two years. Three outcomes were measured: (1) survival; (2) clinical progression (did the person either die, or contract any new or recurrent AIDS- defining opportunistic infection); and (3) treatment failure (death, opportunistic infection, or a 50% or greater drop in CD4 count).

90% of those assigned to the d4T group survived for the two years of the study, vs. 86% of those who stayed with AZT; this is a clear trend in favor of d4T, but did not reach statistical significance due to the small number of deaths. The other two outcomes -- disease progression and treatment failure -- were statistically significant in favor of d4T, however. Switching to d4T resulted in an average three months delay in clinical progression, compared to staying on AZT. (While three months may not seem like much, in actual practice the results are likely to be better than this group average, because those who do best on d4T can stay on it, while others can move on to other drugs or combination treatments. This study was analyzed on an "intent to treat" basis, meaning that those patients randomly assigned to d4T were counted with the d4T averages, even if they could not tolerate the drug -- therefore underestimating the treatment effect.) Throughout the study, CD4 counts were higher by an average of about 40 in those who switched to d4t.

The treatment groups were also analyzed separately by CD4 subset -- 50-100, 100-300, and 300-500. All three groups showed a large "relative risk" in favor of d4T; these were statistically significant in the 50-100 and 300-500 groups.

Viral load (HIV in peripheral blood cells) will be analyzed in this study; blood was collected and plasma HIV RNA will be measured. However, the tests have not been run yet; the only virological data now available is the measurement of virus in blood cells, which was presented to the FDA a year ago.

There were several differences in side effects between the treatment groups, with d4T more likely to cause some side effects, AZT more likely to cause others. Side effects are a concern with d4T; we are hearing that a number of people are unable to tolerate the drug.

This study does not answer a number of other questions about d4T, including how well it may work as initial therapy.

Approval History D4T was approved by the FDA on June 27, 1994. This followed a cautious recommendation for approval by the Antiviral Drugs Advisory Committee, which met on May 20, 1994.

At the time of the May 20 meeting, data from 359 of the 822 patients was available; the other patients were still in the blinded study, so their data could not be used. At that time, those who were assigned to switch to d4T had an average CD4 count about 50 higher than those who continued AZT. The amount of HIV in peripheral blood cells had dropped 53 percent for those on d4T, compared to an 11 percent increase for those on AZT. (This measure of viral load is not the same as the plasma HIV RNA which is more commonly used today, although it is related.) At the May 20 meeting, there were certain technical controversies concerning whether d4T should be approved. These controversies are outlined in "d4T (Stavudine): Approval Recommended," AIDS TREATMENT NEWS #200, June 3, 1994. The main concern is that while blood work showed clear improvement, there was not enough clinical data from the trial yet to prove that those who switched to d4T did better clinically.

The FDA decided to approve d4T under its "Accelerated Approval" regulations, meaning that it granted full approval, but with the requirement that the '019' study be completed, in order to confirm that the benefit seen in blood work would be followed by actual benefit to patients. That confirmation has now been presented.

It is likely that Bristol-Myers Squibb will now ask the FDA to broaden the "labeling" of d4T, so that it will be officially indicated for patients who have taken AZT for six months or longer.

Comment Besides its immediate relevance to drug therapy for HIV, this trial strengthens the evidence that viral load reduction caused by a drug is predictive of clinical benefit. Since patients were assigned at random to one of two courses of therapy (either switch to d4T, or remain on AZT), the difference in viral load (virus in blood cells, in this case -- not virus in blood plasma, which is easier to test and therefore more commonly measured) was clearly caused by the difference in treatment. The big question has been whether a change in viral load caused by a drug will predict a change in clinical outcome for the patient. In this case it did; those in the treatment group which had the lower viral load were also found, a year later, to have done better clinically.

More information will be available when the viral tests are completed.

It also appears that a LARGE increase in CD4 (T-helper) count as a result of drug treatment may be a much better predictor of future clinical improvement than a small CD4 increase.

Acknowledgment AIDS TREATMENT NEWS did not attend the conference in Santa Fe, where these d4T results were presented. We obtained the information from Ben Cheng of Project Inform, who is preparing a more detailed article which will appear in the next issue of PI PERSPECTIVES. You can receive that issue when it comes out by joining the Project Inform mailing list; to do so, call the Project Inform hotline at 800/822-7422 (415/558-9051 in San Francisco), Monday through Saturday10 a.m. to 4 p.m. Pacific time.

Project Inform has set a rare example of putting public interest above organizational considerations in giving us this information and allowing us to publish it before their article comes out. What a contrast to the professional journals which routinely delay important information for months so that they can time its release for maximum advantage to themselves.



 


Copyright © 1995 -AIDS Treatment News, Publisher. All rights reserved to AIDS Treatment News (ATN), Email AIDS Treatment News .

Information in this article was accurate in May 5, 1995. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.