The development of novel HIV integrase inhibitors and the problem of drug resistance

Although all HIV drugs developed to date are prone to the problem of drug resistance, there is hope that second generation integrase inhibitors may prove to be relatively resilient to this problem and to retain efficacy over long periods. This review summarizes information about the integrase mutations identified to date and about why the most recently developed members of this drug class may be superior to earlier drugs. Several newly identified resistance mutations, such as G118R, R263K and S153Y, have been identified through tissue culture selection studies with second-generation integrase strand-transfer inhibitors (INSTIs). These new mutations add to our understanding of the three previously identified resistance pathways involving mutations at positions Y143, N155 and Q148. Biochemical analyses structural modeling, and deep sequencing are methods that currently help in the understanding of the mechanisms of resistance conferred by these various substitutions. Despite the fact that these new resistance mutations confer only low-level cross-resistance to second-generation drugs, the Q148 pathway with numerous secondary mutations has the potential to significantly decrease susceptibility to all members of the INSTI family of drugs. Selection of mutations in vitro with second-generation INSTIs suggests that only low level cross-resistance may exist between these new drugs and first-generation members of this class. The emergence of mutations at position Q148 should be monitored whenever possible and more data are needed to assess the long-term efficacy of second-generation INSTIs in patients who may have failed older INSTIs such as elvitegravir and raltegravir.