Nelfinavir Resistance Appears To Be by a Unique Mutation

Dr. Amy Patick, a virologist with Agouron Pharmaceuticals, presented data on nelfinavir resistance (Abstract #10), confirming preliminary data first presented at the Resistance meetings at Whistler. In the test tube, 22 serial passages of HIV with suboptimal levels of nelfinavir (not unlike a person with incomplete viral suppression) selects for a unique mutation in the protease gene at position 30; D30N. This virus was then tested against other protease inhibitors including saquinavir, indinavir, ritonavir and 141W94 and found to be fully susceptible. Virus isolates from 55 patients treated with nelfinavir, particularly in the early monotherapy studies was examined. 25 were found to have the D30N mutation, leading to about a 4 to 25 fold decrease in susceptibility to nelfinavir. These patient isolates were also still susceptible to other protease inhibitors. Preliminary data from the 511 study found that about 6% of patients treated with AZT, 3TC and nelfinavir developed this mutation.

Testing of recombinant virus constructs with mutations associated with indinavir and ritonavir resistance and patient isolates of indinavir and ritonavir resistant virus (with multiple mutations including position 84) found that these were cross-resistant to nelfinavir.

The preliminary interpretation of these observations suggests that if nelfinavir is the first protease inhibitor used and resistance develops, saquinavir, ritonavir or indinavir might still work. In contrast, if a patient has developed resistance to ritonavir/indinavir, nelfinavir would be unlikely to help. This, along with its modest toxicity would suggest a role for nelfinavir as the first protease inhibitor selected (in combination of course). Caution is necessary, however, since we don't know if virus with the D30N mutation will behave differently when exposed to ritonavir or indinavir.