Mutations Associated with Failure of Raltegravir Treatment Affect Integrase Sensitivity to the Inhibitor In Vitro

Abstract

Raltegravir (MK-0518) is a potent inhibitor of human immunodeficiency virus (HIV) integrase and isclinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received salvage therapy including raltegravir and who subsequently developed virological failure under raltegravir therapy were studied. For each patient, the sequences of the integrase-coding region were determined and compared to that at the beginning of the treatment. Four different mutation profiles were identified in these nine patients: E92Q, G140S Q148H, N155H, and E157Q mutations. For four patients, each harboring a different profile, the wild-type and mutated integrases were produced, purified, and assayed in vitro. All the mutations identified altered the activities of integrase protein: both 3 processing and strand transfer activities were moderately affected in the E92Q mutant; strand transfer was markedly impaired in the N155H mutant; both activities were strongly impaired in the G140S Q148H mutant; and the E157Q mutant was almost completely inactive. The sensitivities of wild-type and mutant integrases to raltegravir were compared. The E92Q and G140S Q148H profiles were each associated with a 7-to 8-fold decrease in sensitivity, and the N155H mutant was more than 14-fold less sensitive to raltegravir. At least four genetic profiles (E92Q, G140S Q148H, N155H, and E157Q) can be associated with in vivo treatment failure and resistance to raltegravir. These mutations led to strong impairment of enzymes in vitro in the absence of raltegravir: strand transfer activity was affected, and in some cases 3 processing was also impaired.

Efficacy and safety of antiretroviral regimens including raltegravir to treat HIV-infected patients with hemophilia

“…No primary or secondary mutations were noted but additional mutations were noted when strains that were resistant to first-line drugs were genotyped. The additional mutations are associated with resistance to several INIs, both in vitro and vivo, but whether they are associated with clinical resistance to raltegravir is unclear (7)(8)(9).…”

Optimized Antiretroviral Therapy with Darunavir/Ritonavir, Etravirine and/or Raltegarvir: A Salvage Therapy Option in HIV-1 Infected Patients with Long-Term Therapeutic Failures, about 23 Cases

“…The development of resistance to integrase inhibitors is a particular concern when raltegravir is by necessity used as monotherapy, or as in the present study, where this molecule was combined to no fully active drugs in the optimized background therapy [17][18][19][20]. The mutations associated with failure of raltegravir treatment affect integrase sensitivity to the virus inhibition and could therefore explain the viral replication in this patient [21]. Moreover, the extensive cross-resistance that exists between NNRTI has limited their use in resistant HIV in- fections.…”

Insights into the Functions of a Molecular Swiss Army Knife: The Intasome Structure Reveals Inhibitor Action

“…Raltegravir (MK-518) [11] was approved for use in patients in late 2007 and elvitegravir (GS9137) [12] is progressing well in Phase III clinical trials. However, in contrast to prior predictions based on in vitro experimentation, raltegravir resistance evolves readily in the clinic [13], necessitating efforts to develop second-generation integrase inhibitors. The rational design of second-generation INSTIs had previously been hampered by the lack of structural information on the binding of these inhibitors to HIV integrase, but the work of Hare et al changes the picture [1].…”