Evolution of HIV integrase resistance mutations

Purpose of Review: Integrase strand transfer inhibitors (INSTIs) have become a key component of antiretroviral therapy since the approval of twice-daily raltegravir in 2007 and the more recent approval of elvitegravir in 2012. At the same time, a third compound, dolutegravir, is in late-phase clinical trials, being tested as part of a multidrug once-daily formulation comprising this INSTI and two other antiretroviral (ARV) drugs. This review focuses on the factors leading to the development of drug resistance mutations (DRMs) against INSTIs, evidence of cross-resistance among them, and the results of regimen simplification in regard to this topic. Recent Findings: Sequencing data show that DRMs are highly dynamic in patients failing INSTI therapy. Considerations of viral fitness and drug resistance can together determine the evolution of drug resistance mutations, and in this regard the Y143 and Q148 pathways are superior to the N155 pathway in the promotion of resistance. Preventing the emergence of DRMs requires that effective reverse transcriptase or other inhibitors be used together with INSTIs and that high-level adherence to treatment be maintained. Summary: Because of the susceptibility to drug resistance, INSTIs should always be used together with other effective ARV drugs.