Business Wire - Monday, November 16, 1998
Patients with this new version of HIV should consider altering their drug regimens, the researchers said. But the researchers also noted that this version of the virus turned up in only a small percentage of the 1,045 HIV- positive patients they studied.
For people carrying HIV that lacks the alteration, a change in drug regimen is not warranted, they said.
HIV is notorious for its ability to change, or mutate, and thereby evade the effects of drugs. Many drugs used to treat HIV interfere with the virus' reverse transcriptase (RT) enzyme, slowing the viral growth rate. Mutations in HIV's RT gene produce an RT enzyme uninhibited by the drugs, allowing the virus to begin growing again.
These mutations result in the exchange of one of RT's many amino-acid building blocks for another. Because such mutations typically enable the virus to resist only one specific RT-inhibiting drug, the patient can still take other RT inhibitors.
The newly identified version of HIV, however, may resist an entire class of RT-inhibiting drugs, the Stanford team found.
In studying HIV isolated from patients who had taken RT inhibitors, the researchers detected mutations resulting in the insertion of two additional amino acids into the viral RT enzyme. When they reconstructed this virus in the laboratory, they found that the insert could, by itself, confer resistance to four of the five currently licensed drugs known as "nucleoside-based" RT inhibitors.
The four drugs were AZT (zidovudine), ddI (didanosine), ddC (zalcitabine) and 3TC (lamivudine).
Moreover, the viruses with inserts isolated from patients usually had additional mutations that also enabled them to resist d4T (stavudine) -- the other licensed drug in this class -- as well as the experimental compound PMEA (adefovir).
The researchers report their findings in the Nov. 15 issue of the Journal of Clinical Investigation. The senior author is Thomas Merigan Jr., MD, Becker Professor of Medicine and director of the Center for AIDS Research at Stanford.
Surprising Change
Other research teams have observed insertions in structural proteins, which make up the outer shell of the virus.
But proteins such as RT and protease serve as the machines - - rather than the structural support -- of the virus, so scientists have assumed that these workhorses would be less tolerant of drastic change.
"We were surprised to find that RT enzymes with additional amino acids were still functional, let alone resistant to RT inhibitors," said research assistant Mark Winters, the study's lead researcher.
Although the insert enabled the virus to resist most nucleoside-based RT inhibitors, it did not affect the potency of other drugs known as "non- nucleoside" RT inhibitors -- for example, nevirapine and efavirenz.
As for the anti-HIV compounds known as protease inhibitors, these drugs act on the protease enzyme rather than the RT enzyme and thus would not be affected by the insert, Winters noted.
Insertion is Rare
Only about 1 percent (10 in 1,045) of the patients studied had viruses with the insert. In a few cases, the Stanford team identified the unusual virus in patients who had enrolled in clinical trials of new drug combinations. But most of the data came from individuals who had requested, through their physicians, to have their viral DNA "sequenced" to determine its genetic makeup, most likely because their current treatment regimens were failing.
The prevalence of the insert in the general population of HIV-positive individuals remains unknown, but the researchers suspect that the insert arises only in patients who have taken RT inhibitors.
"From this study it appears that the insert is not that common of an occurrence. Therefore, I don't believe that the possibility of a patient developing a virus with an insert would cause physicians to change how they initiate therapy," Winters said.
"The insert is something you should look for, and seeing it would let you realize that there are treatment options that are open to you, and (other) options that are no longer open," he added.
For five of the patients studied, the researchers had access to past blood samples and drug histories that enabled them to trace when the insert first appeared. In all of these cases they found that the insert developed during treatment with ddI or ddC, typically in combination with AZT.
Little information is available on whether other RT inhibitors can elicit insert-containing viruses, Winters said.
Additional co-authors at Stanford included research assistants Kristi Coolley, Yvette Girard and Darcy Levee, research associate Robert Shafer, MD, and associate professor of medicine David Katzenstein, MD. Collaborating on the study was Hasnah Hamdan, PhD, of Quest Diagnostics in San Juan Capistrano, Calif.
Funding came from Bristol-Myers Squibb, Hoffmann-LaRoche, the National Foundation for Cancer Research, and the National Institute of Allergy and Infectious Diseases.
CONTACT:
Stanford University Medical Center Office of Communications Mitch Leslie, 650/725-5371 or 723-6911 mleslie@leland.stanford.edu
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