FDA Approves AIDS Drug for Use With AZT
The Food and Drug Administration announced Monday that it has approved the antiviral AIDS drug DDC but only to be used in combination with AZT, the most widely prescribed AIDS antiviral therapy.
Also known as dideoxycytidine and zalcitabine, DDC is the third AIDS antiviral drug to be licensed since 1987, when AZT was approved. Last fall, the FDA approved the antiviral DDI.
Antiviral drugs are considered the major tools in the fight against AIDS because they attack the underlying viral condition, rather than the individual infections and other illnesses that result from a damaged immune system. Most AIDS researchers believe that the key to controlling AIDS ultimately lies in developing an effective combination of antiviral therapies.
“This drug approval represents another step forward for patients with AIDS,” Health and Human Services Secretary Louis W. Sullivan said in a statement. “Zalcitabine has been rapidly developed, tested and reviewed through the cooperative efforts of scientists in the federal government, academia and the pharmaceutical industry.”
The drug is manufactured by Hoffmann-La Roche Inc., of Nutley, N.J.
The agency based its decision on studies showing that the combination regimen produces a dramatic and sustained rise in the number of CD4 cells--the critical immune system cells that are the primary target of the human immunodeficiency virus--compared to patients taking AZT alone.
Early evidence that a drug elevates CD4 cells is not necessarily an indication of how effective it will be. However, an increase in CD4 cells is believed to indicate that the body’s disease-fighting ability has been at least transiently enhanced.
The agency used the same criteria when it approved DDI.
The FDA, which has been seeking to speed AIDS drugs to the market as rapidly as possible, has become increasingly willing to rely on these so-called “surrogate markers” to approve drugs.
At the same time, however, it has insisted on close scrutiny once the drug is marketed and on the continuation of clinical studies to determine whether the drugs are indeed effective.
“In making approval decisions, FDA will use surrogate end points . . . then further confirm its effectiveness through additional human studies . . . after marketing approval,” said FDA Commissioner David A. Kessler. “In this way, we can approve drugs that are both safe and effective as quickly as possible.”
In a sign of the agency’s efforts to speed the approval of AIDS drugs, the action came only eight months after the company submitted its application for licensing. And it was only two months ago that an FDA advisory committee recommended that the agency approve the two drugs to be used in combination therapy--an unusually rapid timetable. Most drug approvals take an average of two years.
“This is particularly heartening because it shows the FDA is continuing its innovative approaches to evaluating AIDS therapies,” said Dr. Robert T. Schooley, an AIDS researcher at the University of Colorado who has conducted studies of DDC.
Dr. Margaret A. Fischl, who directs AIDS programs at the University of Miami school of medicine and also has studied the drug, called the combination treatment “a major advance in the treatment of HIV infection.”
The drug was approved for adults with advanced HIV infection who have CD4 levels fewer than 300 per cubic milliliter of blood and whose normal counts range from 800 to 1,000.
Individuals with advanced AIDS infection who have not yet been treated with any antiviral drugs may now have a difficult decision: whether to take AZT alone--which is now the standard of care in individuals with 500 or fewer CD4 cells per cubic milliliter of blood--or to start by taking both drugs together.
While the combination has resulted in a rise of CD4 cells twice that of AZT alone--in patients who have never taken AZT--it is not yet known whether the two-drug therapy will produce specific clinical benefits, such as improved survival or a delay in developing AIDS-related conditions.
AZT, on the other hand, is known to delay the onset of disease in infected individuals and prolong survival in those with fully developed AIDS.
The combination should be considered “another option” for therapy, said Roche spokesman Paul Oestreicher. “It’s up to the physician to decide what the best course of treatment should be.”
Meanwhile, he added, additional studies of the combination therapy--which include patients who have initially taken AZT--will ultimately answer the question of which course is the most effective.
Roche estimated the average yearly cost of the drug at $1,826. The company said it has established two programs to help patients obtain the drug who cannot afford it.
All of the antiviral drugs produce toxic side effects. DDC can result in peripheral neuropathy, or extremely painful tingling in the hands and feet. Much less frequently, it also can cause inflammation of the pancreas.
AZT is made by Burroughs Wellcome Co. of Research Triangle Park, N.C.
Lifecycle of the AIDS Virus
The AIDS virus replicates by infecting a T-cell, a type of blood cell. Here is how it occurs:
1. Infection begins when the virus binds to the outside of a healthy T-cell and injects its genetic material into the cell.
2. Once inside the cell, genetic material is converted. In a key sequence, viral RNA is changed to viral DNA. This altered viral component migrates to the nucleus, where it is integrated into the T-cell’s genetic code. The T-cell is now infected and no longer can do its job in the body’s immune system.
3. The infected genetic material now serves as a template for the formation of more viral RNA. When produced, this material migrates to the T-cell membrane, and forms a “bud” that is released from the cell.
4. The enzyme proteinase completes the formation of the new infectious HIV virus, which then is free to infect other T-cells in the above manner.
How DDC works: HIVID, the brand name for the new drug, works with AZT to prevent the infection of T-cells by blocking the conversion of viral RNA to viral DNA in the second stage.
Source: Hoffmann-La Rouche
