Broad Phenotypic Cross-Resistance to Elvitegravir in HIV-Infected Patients Failing on Raltegravir-Containing Regimens

Abstract

.5.01; Virco). A control group of patients failing on other regimens was similarly tested. Sixty-one samples were analyzed, 40 of which belonged to patients failing on RAL-containing regimens. Full RAL susceptibility was found in 20/21 controls, while susceptibility to EVG was diminished in 8 subjects, with a median fold change (FC) of 2. T he introduction of highly active antiretroviral therapy (HAART) has transformed the prognosis of HIV-positive patients, with dramatic improvements in survival. However, selection for drug resistance still represents a major challenge and promotes switches in therapeutic regimens for a substantial proportion of patients (3). Virologic failure with some antiretroviral drugs is associated with cross-resistance to agents within the same family, limiting rescue therapeutic options (16). Nevirapine and efavirenz are good examples of crossresistance between members of the same drug family, almost completely sharing resistance patterns. To a lesser extent, this also occurs with failures of some protease inhibitors (12) and nucleoside analogues.Integrase inhibitors (INIs) are a new and promising drug family for the treatment of HIV infection. Raltegravir (RAL) is the first-in-class approved drug for clinical use in both treatmentnaïve (11) and treatment-experienced (19) individuals. Elvitegravir (EVG) will most likely be the second INI compound to be marketed (4). Resistance to INIs has been shown to be driven by changes located mainly in the central domain of the viral integrase. The results of clinical trials and clinical experience have highlighted that failure on RAL-containing regimens is generally driven by the selection of the mutations Y143RHC, Q148HRK, and/or N155H, often accompanied by secondary changes (G140SA, E138K, and L74M, etc.) (2). However, a relatively high proportion of patients does not show such changes upon virologic failure on RAL-containing regimens. Although unidentified resistance mutations might exist, a recent report highlighted that the absence of INI resistance mutations in these individuals is explained mainly by poor drug compliance, given that RAL plasma levels were undetectable in most of them (6).Information about resistance to EVG in vivo is scarce. In the phase II GS-US-183-105 study (13), 28 individuals failed EVG after 24 weeks of treatment. Overall, 39% of them selected the E92Q mutation, 32% selected the Q148HRK mutation, and 25% selected the N155H mutation. Accordingly, broad cross-resistance between RAL and EVG should be expected. The aim of our study was to characterize RAL phenotypic susceptibilities in samples from a group of patients experiencing RAL failure, exploring whether mutations not previously involved in RAL resistance might be recognized and the extent of phenotypic cross-resistance to EVG. MATERIALS AND METHODSStudy population. HIV-1-infected individuals treated at several clinics in Spain who experienced virological failure on a RAL-containing antiretroviral regimen were identified during 2009. Virological failure was defined...

Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

“…DTG, RAL, and EVG have all been recommended as components for first-line therapy regimens in the most recent U.S. DHHS guidelines (13). Clinical data indicate that viruses resistant to the earlier INSTIs (RAL and EVG) have arisen (2,8,10). DTG and GSK1265744 are clearly differentiated as new INSTIs.…”

“…INSTIs are now recognized as a safe and highly effective class of anti-HIV drugs (6). However, clinical resistance to RAL and EVG has been observed, and a high degree of cross-resistance between these two agents has been demonstrated (7,8,9,10,11,12). Furthermore, dosing of RAL is done twice daily, while once-daily administration of EVG requires a pharmacokinetic (PK) booster, such as ritonavir or cobicistat.…”

Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir

“…Each of these pathways is defined by one or more substitutions at specific amino acid positions within the integrase coding region: Y143C or R (here denoted Y143C,R), Q148H,K,R, and N155H (8,(15)(16)(17)(18)(19). Cross-resistance between RAL and EVG has been described for the viruses containing Q148H,K,R and N155H substitutions (20)(21)(22). However, it has been reported that viruses containing amino acid changes at position 143 retain susceptibility to EVG (23).…”

Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors

“…7 RAL has shown failure in the selection of mutations at integrase position Y143, Q148, or N155. 8 Elvitegravir (EVG) (GS-9137) 9 and dolutegravir (DTG) (S/GSK-1349572) 10 are recently approved drugs along with INSTIs, which show improved efficacies against RAL resistant strains ( Figure 1 18 In line with continuous search for a better integrase inhibitor, we have selected dihydroisoquinoline as pharmacophore with a combination of nucleophiles having differential ability to chelate with Mg 2+ ions. Based on these facts, we designed and synthesized three types of 1,2-dihydroisoquinolines derivatives bearing different functional groups at the C-1, C-3, C-7, and N-2 positions (Figure 2).…”