Background drugs and low maraviroc levels explain resistance in Motivate studies

Having only one or no active drugs in the background regimen explained emergence of virus resistant to the CCR5 antagonist maraviroc in the salvage trials MOTIVATE 1 and 2, according to new work by Pfizer researchers [1]. All 4 people in whom maraviroc-resistant virus emerged during the study had low concentrations of the drug.

Thirty-eight of 267 enrollees in the placebo-controlled MOTIVATE trials met criteria for virologic failure with R5-using virus, including 12 in the maraviroc group–7 taking maraviroc once daily and 5 taking maraviroc twice daily. (Maraviroc is licensed for twice-daily dosing.) In 4 of the 12 people with maraviroc failure, Pfizer detected emergence of mutations in the gene that codes for the V3 loop of HIVs envelope protein gp120 [2].

These mutations differed from person to person, but all 4 people still had R5-using HIV when their regimen failed. Three of the four were taking maraviroc once daily. Viral loads before these 4 people started maraviroc ranged from 4.87 to 5.64 log copies/mL, and their CD4 counts ranged from 4 to 177.

To get a better handle on how resistance to maraviroc evolves, the Pfizer team determined viral susceptibility to maraviroc and background regimen drugs in these 4 patients before they started their maraviroc salvage regimen and when that regimen failed. They also measured concentrations of maraviroc in samples collected from patients during the trial.

Maraviroc resistance mutations emerged in 3 people who had no active drugs in their background regimen, according to prestudy resistance tests. The other person in whom maraviroc-related mutations evolved during failure had only one active drug in the background regimen–enfuvirtide–and HIV became resistant to that drug during the trial.

All 4 people in whom maraviroc failed with resistance mutations had low concentrations of the CCR5 antagonist during the study. Two people taking once-daily maraviroc and 1 taking twice-daily maraviroc had average concentrations from 93 to 98 ng/mL–just below the target minimum concentration of 100 ng/mL. The fourth person, who took maraviroc once daily, averaged only 44 ng/mL.

Time to treatment failure measured 49 days, 58 days, and 169 days in the 3 people who had no active drugs except maraviroc in their salvage regimen. In the 1 person with active enfuvirtide in the background regimen, times to treatment failure measured 114 days.

Among the 8 people in whom maraviroc failed with no evidence of resistance mutations, 3 had no active drugs in their background regimen, 2 had one active drug (amprenavir or abacavir), 2 had two active drugs (3TC/abacavir or tenofovir/atazanavir/ritonavir), and 1 had three active drugs (3TC/abacavir plus lopinavir/ritonavir). Maraviroc concentrations were good in 2 of these 8 (205 and 268 ng/mL), marginally low in another 2, one of whom temporarily discontinued maraviroc (97 and 94 ng/mL), and very low in the other 4 (1 to 50 ng/mL).