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Overlooked Mutation Can Spur HIV Drug Resistance

It should be added to standard genetic tests used to guide treatment, experts say

SATURDAY, Dec. 1 (HealthDay News) -- One in 10 HIV-infected people receiving drug treatment harbors a hidden genetic mutation that renders certain strains of the virus more resistant to antiretroviral medications, researchers say.

Their study suggests that the N3481 mutation should now be added to standard HIV gene tests that AIDS specialists use as they decide which cocktail of drugs a patient should receive.

"The importance of N3481 is also underscored by the fact that it appears relatively early after starting drug therapy," noted study senior author Gilda Tachedjian, head of the Molecular Interactions Group at the Macfarlane Burnet Institute for Medical Research and Public Health, in Melbourne, Australia.

The mutation, largely overlooked by researchers, appears to confer resistance to zidovudine (AZT or Retrovir), the first drug ever approved to fight HIV; and nevirapine (Viramune), one of a group of powerful antiretroviral medications.

Both medicines fall into a broad category of drugs called reverse transcriptase inhibitors (RTIs), so named because they target a key enzyme on HIV called reverse transcriptase.

Tachedjian's group published its findings late Friday in the December issue of PLoS Medicine on the eve of World AIDS Day.

Gene tests aimed at gauging a particular strain of HIV's resistance to common AIDS drugs are routine in clinical practice, noted Mattias Gotte, an associate professor of microbiology and immunology at McGill University in Montreal. Gotte is also the author of an accompanying commentary in the journal.

"You go as an infected person to a clinician, and you get a certain regimen. Most of the time the clinician uses genotyping [gene tests] to see whether certain preexisting mutations may compromise therapy," he explained. "The other thing that happens is when you are on a failing regimen. Then, the clinician would genotype the virus and eventually base his or her decision on the results."

The trick is to match the patient's version of HIV to a group of drugs that will be least prone to resistance.

In the case of nevirapine and other widely used RTIs, AIDS experts thought they knew where the key points of resistance lay on the reverse transcriptase molecule, and so they designed their tests accordingly.

"Genotyping assays currently look for drug-resistance mutations in the first two-thirds (N-terminal region) of the reverse transcriptase," Tachedjian explained. "The reason for this is that it is where most of the important resistance mutations have occurred."

But there's another region on the enzyme, called the C-terminal, that's also essential to proper reverse transcriptase function.

"Our logic for the current study was that since the C-terminal region is involved in how the enzyme 'works,' then it is likely that drug resistance mutations could [also] emerge in this region," Tachedjian said.

In their study, her team analyzed samples from more than 1,000 HIV patients who had received antiretroviral drug therapy. They then compared their results to samples taken from 368 HIV-positive patients who had not yet undergone drug therapy.

The C-Terminal N3481 mutation turned up in 12 percent of patients who'd been exposed to HIV-suppressing drugs, the researchers report.

In contrast, fewer than 1 percent of the not-treated patients had the resistance-linked mutation -- suggesting that it developed after the virus had been exposed to AIDS drugs.

"The N3481 mutation is different from most of the other mutations described to date because it confers some level of resistance to nevirapine and zidovudine, which are drugs belonging to two different classes of reverse transcriptase inhibitors," Tachedjian pointed out. "N3481 can work alone to confer resistance to nevirapine and zidovudine and can augment resistance when in the presence of other drug mutations found in the N-terminal region of the enzyme."

The trouble is, standard genotyping tests are designed to pick up N-terminal mutations but they ignore the C-terminal region, including N3481.

According to Tachedjian, that means the finding "may have implications for genotypic resistance testing, particularly for patients on zidovudine and nevirapine therapy, and therefore should be considered for incorporation in [standard] genotyping assays."

The advent of new antiretroviral drugs means these gene tests are already going to have to be altered, she added, "and while we are making these changes it could be relatively straightforward to include" the C-terminal region, and N3481, in the tests as well.

Tachedjian believes other overlooked, resistance-conferring mutations might also be hiding out in the C-terminal region, and her team is currently looking into that possibility.

In the meantime, the N3481 discovery could have implications for AIDS drug development, Gotte pointed out.

"We learn a lot when we study mechanisms of resistance, in terms of what we should avoid in regard to drug development and how we can make drugs better," he said.

Gotte stressed that HIV-positive patients should not be overly concerned that their doctors are missing a key factor as they seek to determine the best treatment strategy.

While adding N3481 to the genotyping mix will improve treatment design, "it's still a minor piece of the puzzle that's missing here," he said. "I wouldn't be too worried about this because clinicians also look for other parameters" as they choose effective therapies, he added.

More information

Find out more about HIV at the U.S. National Institute of Allergy and Infectious Diseases.

SOURCES: Gilda Tachedjian, Ph.D., Senior Burnet Fellow and head, Molecular Interactions Group, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia; Mattias Gotte, Ph.D., associate professor, department of microbiology and immunology, McGill University, Montreal, Canada; December 2007 PLoS Medicine

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