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

• DOI: 10.1128/aac.01228-07
• Publication Date: 2008-01-29T01:46:57Z
• Authors: Isabelle Malet; Olivier Delelis; Marc-Antoine Vala...; Brigitte Montes; Cathia Soulie; Marc Wirden; Luba Tchertanov; Gilles Peytavin; Jacques Reynes; Jean-François Mo...; Christine Katlama; Vincent Calvez; Anne-Geneviève M...
• Keywords: Raltegravir; Integrases; Integrase inhibitor; Elvitegravir; Dolutegravir

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