It has been discovered that over 60 variations of INSTI mutations cause in vivo and in vitro resistance. Due to these mutations and development of resistance the inhibitors are less effective against the virus.
Resistance of INI corresponds to those of other ARV drugs. First IN  resistance is caused by primary mutations that decrease INI sensitivity in combination with secondary mutations that further reduce virus sensitivity and/or repair decreased fitness of the virus. Secondly there is a genetic barrier to INI resistance, defined by the number of mutations required for the loss of clinical INI activity. Thirdly there is extensive but incomplete cross-resistance among the INIs.
A loop containing amino acid residues 140–149 is located in the catalytic-core domain and is important for IN function as mentioned before. This loop is flexible and even though its role is not quite known it is thought to be important and its functions critical for DNA binding. This resistance appears within mutations in this IN-coding region.
The resistance to raltegravir and elvitegravir is primarily due to the same two mutation pathways but other primary mutations are also involved for each of the drugs. Some mutations increase resistance to the drugs to a large extent than others. For example, one of the most common mutation pathway increases the resistance to raltegravir up to 100 times more than the second most common one.
Resistance to Integrase Inhibitor S/GSK1349572 is still being developed and the resistance has not been fully characterized. When it was assessed alongside the primary mutations of raltegravir and elvitegravir it did not show cross-resistance which means that it could be useful against drug resistant viruses.
Raltegravir has limited intestinal absorption and thus resistance cannot be overcome by prescribing higher doses. Newer drugs are warranted to overcome this pharmacological disadvantage and gain plasma concentrations high enough to target raltegravir-resistant viruses.