Resistance to HIV integrase inhibitors.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Thibault
T
Mesplède
Peter K
PK
Quashie
Mark A
MA
Wainberg
D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D020125:Mutation, Missense
D019428:HIV Integrase Inhibitors; D019427:HIV Integrase