HIV integrase inhibitors are potent antiretroviral drugs that efficiently decrease viral load in patients. Emergence of resistance mutations against this new class of drugs represents a threat to their long-term efficacy. The purpose of this review is to provide new information about the most recent mutations identified and other mutations that confer resistance to several integrase inhibitors.
New resistance mutations, such as G118R, R263K and S153Y, have been recently identified through in-vitro selection studies with second-generation integrase strand-transfer inhibitors (INSTIs). These add to the three main resistance pathways involving mutations at positions Y143, N155 and Q148. Structural modeling, biochemical analyses and deep sequencing are methods that currently help in the understanding of the mechanisms of resistance conferred by these mutations. Although these new resistance mutations appear to confer only low levels of cross-resistance to second-generation drugs, the Q148 pathway with numerous secondary mutations has the potential to significantly decrease susceptibility to all drugs of the INSTI family.
Recent mutations selected in vitro with second-generation INSTIs suggest the existence of low levels of cross-resistance between these drugs and first-generation compounds. In clinical practice, the emergence of mutations at position Q148 should be monitored whenever possible. More datasets are needed to assess the long-term efficacy of second-generation INSTIs in patients failing older INSTIs such as raltegravir and elvitegravir.
aMcGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital
bDivision of Experimental Medicine
cDepartment of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
Correspondence to Mark A. Wainberg, McGill University AIDS Centre, Jewish General Hospital, 3755 Cote Sainte Catherine, Montreal, QC H3T 1E2, Canada. Tel: +1 514 340 8222 x5282; fax: +1 514 340 7537; e-mail: firstname.lastname@example.org