Plus a Comment by Dr. Joel Gallant

Reports of new research published in the August issues of Nature Medicine and Nature Structural Biology raise questions for people with HIV disease who are considering their treatment options.

The research suggests that AZT, an agent in the class of drugs called thymidine analogs, is less effective than it might be due to a fundamental flaw in its chemical structure. This flaw prevents AZT from being efficiently metabolized in the body. As a result, less AZT is converted to an active form that is able to attack HIV. Researchers suggest this structural flaw as the explanation for some of the resistance that develops with prolonged AZT use, as well as for some of the side effects associated with AZT.

Recently, the U.S. Department of Health and Human Services (HHS) issued a draft of Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, which underscores the importance of including a thymidine analog in every combination antiretroviral regimen. AZT was the first thymidine analog to be made available to treat HIV disease. A second-generation drug of this same class is d4T, which later was designed to more closely resemble the naturally occurring substance, thymidine. Because of this structural difference, d4T does not have the flaw described in this research. The result is that d4T is more actively metabolized, to a form that makes more drug available to efficiently attack the HIV virus. AZT and d4T, while not taken together, are paired with the non-thymidine analogs, ddI, ddC and 3TC, as cornerstones of combination therapies.

"The use of antiviral therapies makes a tremendous difference in the lives of many people living with HIV disease," stated Cornelius Baker, executive director of the National Association of People with AIDS (NAPWA) and member of the Panel on Clinical Practices for the Treatment of HIV Infection, which developed the HHS Guidelines. "It is essential that individuals on antiviral therapies continue to take their medications as prescribed, and that they discuss the implications of these findings with their physicians." noted Baker. "This new research provides important information and advances the medical understanding of the treatment of this disease," Baker added.

"It is important that physicians and patients understand and consider the similarities and differences between the available thymidine analogs when making treatment decisions," commented Calvin J. Cohen, M.D., research director, Community Research Initiative of New England. "Several small clinical trials have begun to provide important clinical information comparing AZT and d4T. Additional large-scale studies comparing these two agents in combination with other drugs will help clinicians make treatment decisions in the context of the HHS guidelines. These findings will be particularly important in light of the new research on AZT's structure and its clinical implications."

Since 1983, the National Association of People with AIDS (NAPWA) has been at the forefront of giving voice to the often silent lives of people living with AIDS. NAPWA devotes its daily attention to focusing on the ways we can prevent the spread of HIV and working diligently toward finding a cure. NAPWA's mission is broad, but its vision is simple...a world without AIDS.

For more information on NAPWA's treatment education programs or to receive a copy of Do You Know Your Options? An Updated Guide to Antiretroviral Therapies (2nd edition), call 202-898-0414, or write to NAPWA at 1413 K Street NW, Washington, DC 20005, http://www.napwa.org.

Contact: Ernest Hopkins, NAPWA
(202) 898-0414
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Comment by Joel Gallant

This report should not change anyone's approach to therapy; it simply provides us with a better explanation for what we've known for years: that AZT monotherapy provides modest and time-limited benefit and that the development of resistance to AZT is one of the most important factors limiting its efficacy.

If you're taking AZT along with another reverse transcriptase inhibitor and a protease inhibitor and you have an undetectable viral load, the fact that AZT isn't perfect doesn't lessen your success. We don't know how to do better than suppressing the virus to undetectable levels. The fact that resistance to AZT occurs faster than resistance to d4T is irrelevant in this situation, since resistance may not occur at all when viral replication is being completely suppressed by protease inhibitors.

For all its flaws, we'd be left with a lot fewer options if we eliminated AZT from our arsenal, especially since AZT is unique in that resistance can be prevented or reversed by the coadministration of 3TC (and perhaps delavirdine). Furthermore, we shouldn't forget that AZT (even by itself) has not only been shown to prolong life, but to prevent transmission from mother to infant, to prevent infection of health care workers after needle sticks, to prevent and treat dementia, and to reverse HIV-related thrombocytopenia (low platelet count).

In summary, we've always know that AZT is an imperfect drug. Now, with the increasing transmission of AZT-resistant virus and the much greater potency of newer therapies, the imperfections of AZT are even more obvious. This study provides us with a better understanding of a potential mechanism for AZT's weakness, but it doesn't change the fact that without the availability of AZT as an adjunct to more effective antiretroviral agents, our options would be seriously limited.