Overlooked Mutation Can Spur HIV Drug Resistance

Overlooked Mutation Can Spur HIV Drug Resistance
SATURDAY, Dec. 1 (HealthDay News) -- One in 10 HIV-infectedpeople receiving drug treatment harbors a hidden genetic mutation thatrenders certain strains of the virus more resistant to antiretroviralmedications, researchers say.
Their study suggests that the N348I mutation should now be added tostandard HIV gene tests that AIDS specialists use as they decide whichcocktail of drugs a patient should receive.
"The importance of N348I is also underscored by the fact that itappears relatively early after starting drug therapy," noted study seniorauthor Gilda Tachedjian, head of the Molecular Interactions Group at theMacfarlane Burnet Institute for Medical Research and Public Health, inMelbourne, Australia.
The mutation, largely overlooked by researchers, appears to conferresistance to zidovudine (AZT or Retrovir), the first drug ever approvedto fight HIV; and nevirapine (Viramune), one of a group of powerfulantiretroviral medications.
Both medicines fall into a broad category of drugs called reversetranscriptase inhibitors (RTIs), so named because they target a key enzymeon HIV called reverse transcriptase.
Tachedjian's group published its findings late Friday in the Decemberissue of PLoS Medicine on the eve of World AIDS Day.
Gene tests aimed at gauging a particular strain of HIV's resistance tocommon AIDS drugs are routine in clinical practice, noted Mattias Gotte,an associate professor of microbiology and immunology at McGill Universityin Montreal. Gotte is also the author of an accompanying commentary in thejournal.
"You go as an infected person to a clinician, and you get a certainregimen. Most of the time the clinician uses genotyping [gene tests] tosee whether certain preexisting mutations may compromise therapy," heexplained. "The other thing that happens is when you are on a failingregimen. Then, the clinician would genotype the virus and eventually basehis or her decision on the results."
The trick is to match the patient's version of HIV to a group of drugsthat will be least prone to resistance.
In the case of nevirapine and other widely used RTIs, AIDS expertsthought they knew where the key points of resistance lay on the reversetranscriptase molecule, and so they designed their tests accordingly.
"Genotyping assays currently look for drug-resistance mutations in thefirst two-thirds (N-terminal region) of the reverse transcriptase,"Tachedjian explained. "The reason for this is that it is where most of theimportant resistance mutations have occurred."
But there's another region on the enzyme, called the C-terminal, that'salso essential to proper reverse transcriptase function.
"Our logic for the current study was that since the C-terminal regionis involved in how the enzyme 'works,' then it is likely that drugresistance mutations could [also] emerge in this region," Tachedjiansaid.
In their study, her team analyzed samples from more than 1,000 HIVpatients who had received antiretroviral drug therapy. They then comparedtheir results to samples taken from 368 HIV-positive patients who had notyet undergone drug therapy.
The C-Terminal N348I mutation turned up in 12 percent of patients who'dbeen exposed to HIV-suppressing drugs, the researchers report.
In contrast, fewer than 1 percent of the not-treated patients had theresistance-linked mutation -- suggesting that it developed after the virushad been exposed to AIDS drugs.
"The N348I mutation is different from most of the other mutationsdescribed to date because it confers some level of resistance tonevirapine and zidovudine, which are drugs belonging to two differentclasses of reverse transcriptase inhibitors," Tachedjian pointed out."N348I can work alone to confer resistance to nevirapine and zidovudineand can augment resistance when in the presence of other drug mutationsfound in the N-terminal region of the enzyme."
The trouble is, standard genotyping tests are designed to pick upN-terminal mutations but they ignore the C-terminal region, includingN348I.
According to Tachedjian, that means the finding "may have implicationsfor genotypic resistance testing, particularly for patients on zidovudineand nevirapine therapy, and therefore should be considered forincorporation in [standard] genotyping assays."
The advent of new antiretroviral drugs means these gene tests arealready going to have to be altered, she added, "and while we are makingthese changes it could be relatively straightforward to include" theC-terminal region, and N348I, in the tests as well.
Tachedjian believes other overlooked, resistance-conferring mutationsmight also be hiding out in the C-terminal region, and her team iscurrently looking into that possibility.
In the meantime, the N348I discovery could have implications for AIDSdrug development, Gotte pointed out.
"We learn a lot when we study mechanisms of resistance, in terms ofwhat we should avoid in regard to drug development and how we can makedrugs better," he said.
Gotte stressed that HIV-positive patients should not be overlyconcerned that their doctors are missing a key factor as they seek todetermine the best treatment strategy.
While adding N348I to the genotyping mix will improve treatment design,"it's still a minor piece of the puzzle that's missing here," he said. "Iwouldn't be too worried about this because clinicians also look for otherparameters" as they choose effective therapies, he added.