Overlooked Mutation Can Spur HIV Drug Resistance

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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 N348I 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 N348I 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. "N348I 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 N348I.

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."