Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy^*

Abstract

ObjectivesRecent data showed the selection of mutations in the integrase gene, mainly involving position 148 or 155, in patients displaying virological failure (VF) on raltegravir (RAL) therapy. Here, we describe the development of RAL resistance, in both plasmatic and cellular compartments, in three heavily pretreated HIV-infected patients failing RAL-containing regimens. MethodsThree of 17 patients receiving RAL displayed VF. The entire integrase gene, isolated from plasma and peripheral blood mononuclear cells (PBMC), was sequenced. A clonal analysis was performed in one patient at the time of VF. ResultsAt the time of VF, RAL-resistance mutations were selected: (i) Q148R in patients 1 and 3; (ii) T66A and E92Q in patient 2. A gradual accumulation of new mutations was observed in all patients, including G140S, Q148H and N155H in patient 1, L74I in patient 2, and G140S in patient 3. Clonal analysis showed the coexistence, in patient 1, of the two common resistance pathways (mutations Q148R/H and N155H) found in distinct quasi-species. In addition, RAL-resistance mutations were detected in HIV DNA in all patients. ConclusionsHaving rapidly established, resistance to RAL evolves and diversifies, and is likely to impact the efficacy of subsequently used second-generation integrase inhibitors. Moreover, RAL-resistance mutations can be archived early in PBMC.

Loss of Raltegravir Susceptibility by Human Immunodeficiency Virus Type 1 Is Conferred via Multiple Nonoverlapping Genetic Pathways

“…In addition, the secondary mutation E92Q preferentially resides on virus clones bearing the N155H mutation while G140S(A) is selected by viruses bearing mutations at position 148. In this study population (a subset of virologic failures from BENCHMRK I and II), the identification of E92Q in the absence of N155H was rare (1/69 RAL failures), consistent with other reports (4,20). We also observed primary IN mutations at position 143, albeit at a low frequency (4/69 or 6%) compared to the selection of mutations at position 155 only (31/69 or 45%) and 148 only (R, H, K; 20/69 or 29%) at the time of the first virologic failure.…”

“…Recently, several reports have described the evolution of IN resistance mutations under continued RAL pressure in the absence of complete viral suppression (4,6,21 . Additional case studies have also documented evolution from N155N/H to Q148H (4) or N155H to Y143R in subjects with incomplete viral suppression (6).…”

Comparative antiviral activity of integrase inhibitors in human monocyte-derived macrophages and lymphocytes

“…This may result in a perturbed infection of T-lymphocytes and subsequent altered apoptosis. In fact, it is already known that M/M can recruit lymphocytes and trigger their death, through several events, mediated by viral proteins (such as nef and gp120), or by chemokines and other factors produced during HIV-1 infection (Badley et al, 1997;Charpentier et al, 2008).…”

Substitutions at Amino Acid Positions 143, 148, and 155 of HIV-1 Integrase Define Distinct Genetic Barriers to Raltegravir Resistance In Vivo

“…Specifically, in RAL phase II and III clinical trials, investigators noted that N155H variants detected at the first fail-ure time point were frequently replaced by Q148H, K, or R variants at later time points in the presence of ongoing RAL exposure (22,23). Other groups have also reported shifts from N155H to Q148H (3,21,24), as well as shifts from N155H to Y143R (5).…”

“…For the most part, RAL-and EVG-resistant variants remain susceptible to DLG (S/GSK1349572), which, in vitro, selects for a distinct mutation profile that includes L101I, T124A, and S153F or Y (16). A notable exception may be viruses containing mutations at position 148, which in vitro can exhibit reduced susceptibility to DLG when they also contain specific secondary mutations (16) Studies evaluating sequential virus samples have reported shifts in primary IN inhibitor resistance mutation patterns in subjects remaining on RAL following virologic treatment failure (3,5,9,20,22,23). Specifically, in RAL phase II and III clinical trials, investigators noted that N155H variants detected at the first fail-ure time point were frequently replaced by Q148H, K, or R variants at later time points in the presence of ongoing RAL exposure (22,23).…”