 |
|
|
| |
Maraviroc Failure With X4 Virus Does Not Spur New Resistance to Other ARVs
|
| |
| |
Targeting HIV Entry: 3rd International Workshop
December 7-9, 2007
Washington, DC
Mark Mascolini
Failure of a maraviroc-based salvage regimen with emergence of CXCR4 (X4)-using virus did not lead to widespread resistance to nucleosides, nonnucleosides, protease inhibitors (PIs), or enfuvirtide, at least not in 6 patients studied through 24 weeks of the MOTIVATE 1 and 2 trials [1].
Earlier work by Pfizer traced most X4-using HIV that appeared during maraviroc failure to pretreatment pockets of X4 virus in heavily pretreated people starting the CCR5 antagonist with other antiretrovirals (ARVs) in MOTIVATE 1 and 2 [2]. But X4 virus detected in 6 of 20 people in this earlier analysis did not come from hidden pre-maraviroc reservoirs of X4-using HIV.
To map evolution of resistance to other ARVs during salvage failure in these 6 people, the Pfizer team compared their presalvage and failure genotypes. Five of these 6 people were taking maraviroc in the trials, while the sixth got randomized to placebo. Two of the 5 maraviroc-treated patients were still taking the CCR5 antagonist at study week 24. Pfizer matched genotypes from viral samples collected 4 to 6 weeks before the study began with genotypes from samples gathered upon maraviroc failure, or at week 24 in the 2 people who did not meet study definitions of failure but had a detectable viral load.
Prestudy genotyping consistently detected virus already resistant to three or four ARV classes, consistent with the MOTIVATE goal of recruiting people with deep antiretroviral experience. Baseline mutations reflected the antiretrovirals people had taken to this point. Virus from the group in this subanalysis carried an average of 11 PI mutations, eight nucleoside mutations, and one nonnucleoside mutation. Three of the six people had virus resistant to enfuvirtide.
Almost all mutations detected in R5-using virus at screening for the trials showed up in X4-using virus at failure. Among people taking maraviroc in the trial, four new mutations emerged upon failure in one person, two news mutations in another, and one new mutation in two other people. All new mutations that arose in these people reflected drugs used in the optimal background regimen with maraviroc.
Most new mutations that appeared during maraviroc therapy involved the protease gene, and most of these were minor or accessory mutations (K20V, K20R, I131V) in people who already had plentiful PI mutations. The enfuvirtide-related V38A mutation arose in the one person with four new mutations.
Pfizer concluded that their analysis yielded "no evidence of different resistance profiles archived or emerging in the CXCR4-using virus population."
References
1. Lewis M, Simpson P, van der Ryst E, Westby M. Analysis of the protease inhibitor/reverse transcriptase inhibitor/fusion inhibitor resistance pattern of treatment-emergent CXCR4-using virus from 6 patients in the MOTIVATE studies shows no evidence of different drug resistance profiles being archived in the CCR5-tropic vs CXCR4-using populations. Targeting HIV Entry: 3rd International Workshop. December 7-9, 2007. Washington, DC. Abstract 6.
2. Lewis M, Simpson P, Fransen S, et al. CXCR4-using virus detected in patients receiving maraviroc in the phase III studies MOTIVATE 1 and 2 originates from a pre-existing minority of CXCR4-using virus. Antiviral Therapy. 2007;12:S65. Abstract 56.
|
| |
|
|
|
|
|
