Resistance

Three distinct pathways for raltegravir (RAL) resistance seem to exist and they are marked by primary mutations at 143, 148, and 155, with 148 being the preferred mutation. These mutations are thought to be mutually exclusive, e.g., a person can have some virus that uses the N155H pathway and other virus that uses the Q148K/R/H pathway, but these mutations will not appear together on the same viral genome.

BENCHMRK study participants who showed a difference in genotypic data between baseline and virological failure were studied to identify patterns of resistance. The following was discovered:

  • Mutations occur over time, that is, the number of persons who had a single resistance mutation at the time of treatment failure was 30%. At the time of the last genotyping test, only 8% had a single mutation and the rest had acquired multiple mutations.
  • The three distinct signature mutations were at N155, Q148, and Y143. In the beginning, the N155 was most common, but Q148H was the dominant mutation over time.
  • The N155 mutation alone reduced RAL sensitivity 10-fold. The secondary mutations that usually followed could reduce sensitivity by 100-fold.

In vitro studies indicate this interesting concept: RAL seems to remain effective against HIV for a period longer than its metabolic half-life. Because of its unique binding capacity, RAL is able to bind to viral DNA in such a way that it is permanently inactivated. Thus, resistance is not dose-dependent. RAL could still be active against HIV in a cell that has been exposed to drug, even in patients with high viral load, depleted CD4 cell counts, and low sensitivity to the drug.1 2 

Resistance patterns were examined in one small French study. Through sequencing the entire integrase gene in three (out of 17) patients in whom resistance mutations to RAL were quickly established, the following observations were made about RAL resistance:

  • It evolves and diversifies.
  • Resistance is archived early in peripheral blood mononuclear cells.
  • This could limit the efficacy of any second-generation integrase inhibitor. 

In one patient, both of the common resistance pathways were found (Q148R/H and N155H). Other resistance mutations included T66A, E92Q, G140S, and L74I.3 

References

  1. Hazuda DJ et al. Analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from the Benchmrk 1 and 2. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-898, 2008
  2. Cooper DA et al. Subgroup and resistance analysis of raltegravir for resistant HIV-1 infection. N Engl J Med 359(4): 355-365, 2008
  3. Charpentier C et al. Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy. HIV Medicine [Epub ahead of print 21 july] DOI: 10.1111/j.1468-1293.2008.00628, 2008
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