 |
|
|
| |
Maraviroc Analysis Highlights Difficulties in Defining Resistance
|
| |
| |
XVI International HIV Drug Resistance Workshop
June 12-16, 2007
Barbados
Mark Mascolini
Analysis of virus from maraviroc-treated people in the phase 3 MOTIVATE trials determined that mutations in the V3 loop of viral envelope play a key role in emergence of resistance to this drug, but the mutations differed from person to person [1]. That conclusion appeared to contradict Monogram Biosciences evidence that mutations outside the V3 loop contribute to resistance to CCR5 antagonists and may be necessary for high-level resistance to these drugs [2]. (NATAP will provide a separate review of the Monogram study.)
Resistance to maraviroc is complicated because resistant viruses generated in cell studies appeared to use CCR5 coreceptors left unblocked by maraviroc or receptors that maraviroc plugged. (A clinical trial of vicriviroc, another CCR5 antagonist, found evidence "suggesting improved efficiency of viral entry using vicriviroc-bound CCR5" [3]. NATAP is reviewing that study separately.) To reach a better understanding of how resistant HIV outmaneuvers maraviroc, Pfizer investigators tried to identify markers of resistance in MOTIVATE trial participants in whom maraviroc failed even though HIV continued to use CCR5.
The dual resistance mechanism identified in cell studies is marked by a dose-response curve indicating a reduced maximal percentage inhibition (MPI) with maraviroc. So the Pfizer researchers studied people whose MPI plateaued below 95% when taking the drug. MOTIVATE participants were also eligible for the resistance study if they met one of two other criteria: a fold change in 50% inhibitory concentration (IC50) outside the normal range for maraviroc (above 1.95-fold), or more than a 2-fold change in IC50 when comparing on-treatment virus with pretreatment virus.
MPI never plateaued below 95% in 38 pretreatment viral samples from people randomized to take maraviroc or in 25 on-treatment viral isolates from people in whom placebo plus other antiretrovirals failed. But MPI did fall short of 95% in 4 of 12 people in whom a maraviroc regimen failed. Susceptibility to maraviroc, measured as fold change in IC50, did not correlate with maraviroc failure. The largest change in IC50 from pretreatment to on-treatment virus was only 3-fold.
Pfizer compared pretreatment and on-treatment V3 loop sequences from virus sampled from the 4 patients with an MPI plateau below 95%. All had changes in the V3 loop; although these mutations differed from person to person, all 4 people had mutations at V3 positions 13 or 26. Mutations that arose in the ACTG trial of vicriviroc also varied from person to person. Entry inhibitor experts believe this inconsistency reflects the heterogeneity of V3.
Experiments incorporating the maraviroc-related mutations into viral constructs (site-directed mutatgenesis) confirmed that these V3 loop mutations make virus resistant to maraviroc. In site-directed mutants derived from one person, the mutations 13S plus 16Ains were sufficient to cause resistance to maraviroc in the pretreatment virus and necessary for resistance in the failure isolate. For the second person, the mutations 20F plus 25D plus 26V were sufficient to cause resistance in the pretreatment virus and necessary in the failure virus. For the third person, 11S plus 26V were not sufficient for resistance in the pretreatment virus but necessary for resistance in the failure virus. And for the fourth person, 13H alone was sufficient for resistance in the pretreatment virus and necessary for resistance in the failure virus.
This diversity in resistance patterns suggested to the Pfizer group that genotypic algorithms predicting resistance to CCR5 antagonists will be tough to devise. But in the 4 people in whom V3 mutations emerged, an MPI below 95% looked like a reasonable marker of resistance. Perhaps the more unsettling outcome of this study is that two thirds of the people in whom maraviroc failed with CCR5 virus had no phenotypic marker of resistance to this drug.
References
1. Mori J, Mosley M, Lewis M, et al. Characterization of maraviroc resistance in patients failing treatment with CCR5-tropic virus in MOTIVATE 1 and MOTIVATE 2. Antiviral Therapy 2007;12:S12. Abstract 10.
2. Huang W, Wojcik L, Toma J, et al. Mutations in the coreceptor binding region of the
HIV-1 envelope confer resistance to the CCR5 inhibitor SCH-C (SCH 351125). Antiviral Therapy 2007;12:S134. Abstract 121.
3. Tsibris AMN, Gulick RM, Su Z, et al. In vivo emergence of HIV-1 resistance to the CCR5 antagonist vicriviroc: findings from ACTG A5211. Antiviral Therapy. 2007;12:S15. Abstract 13.
|
| |
|
|
|
|
|
