A presentation at the 2008 ICAAC in Washington, DC helps deepen our understanding of Merck's integrase inhibitor, Isentress (raltegravir). The talk by Daria Hazuda showed how resistance develops to Isentress and poses a possible explanation for its unparalleled ability to reduce HIV levels quickly.
Hazuda reported on an analysis of the BENCHMRK 1 and 2 studies, which were the basis for Isentress' FDA approval. In these studies, people with extensive experience taking HIV drugs were randomly assigned to take either Isentress or a placebo, each taken with optimized background therapy (or the best available combination of HIV drugs chosen with the aid of resistance testing).
Overall it was rare to develop resistance to Isentress in these studies. When people did, they tended to develop mutations that had been seen in earlier research, particularly at positions 148 and 155. This analysis found that over time people tended to accumulate more resistance mutations, and the pattern of mutations tended to evolve from mostly 148 to mostly 155. This may be important, as the 155 mutation is more damaging to HIV's ability to replicate, called viral fitness, than 148.
Perhaps of more interest is the finding that the likelihood of experiencing treatment failure on Isentress was not related to concentrations of the drug measured in the blood. Rather, it seems to be related to the amount of time the drug remains bound or attached to the integrase enzyme, called its off-rate.
It appears that Isentress, and other integrase inhibitors, stay attached to the integrase-HIV complex longer than they are measurable in the blood. This might explain why Isentress reduces HIV levels more quickly than other HIV drugs, as it retains activity longer than it is measurable in the blood.
Isentress has proven a very successful option for many people who had few HIV treatment options. Resistance to Isentress remains rare, but this study helps us better understand how it does develop. It also may help us understand the drug's unique ability to reduce HIV levels more quickly than other drugs.