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Background Drugs and Bad Adherence Explain Most Maraviroc Failures
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
Lack of active drugs in optimized background regimens and poor adherence emerged as key reasons behind maraviroc failure in people with CCR5-using HIV during the MOTIVATE-1 and -2 salvage trials, according to an analysis by Pfizer's Julie Mori [1]. Resistance mutations that evolved in some people taking a failing regimen revealed no particular pattern.
Earlier Pfizer work established two routes to failure of this CCR5 antagonist in the MOTIVATE studies [2]
· Emergence of CXCR4-using virus during maraviroc salvage
· Selection of maraviroc-resistant CCR5-using virus
To uncover the reasons behind failure with R5 virus, Mori used the PhenoSense Entry assay to compare pretreatment and on-treatment viral isolates from 36 people in whom maraviroc failed to control CCR5-using HIV. For samples with phenotypic evidence of resistance--a maximal percentage inhibition (MPI) below 95%--she analyzed clones of resistant virus.
Viral load in these 36 people at study entry averaged 5.1 log (just over 100,000 copies), and their CD4 counts ranged from 3 to 812 (mean 139). Time to protocol-defined treatment failure averaged 95 days and ranged from 17 to 180 days. Among 34 people whose viral subtype was characterized, all had subtype B virus.
Fifteen of the 36 people with maraviroc failure (42%) had an MPI below 95% at failure, which Pfizer regards as a clinical marker of resistance to this CCR5 antagonist. As Harvard's Daniel Kuritzkes explained in an invited lecture at this workshop, phenotypic evidence of resistance to noncompetitive inhibitors like CCR5 antagonists differs from such evidence with competitive inhibitors like protease and reverse transcriptase inhibitors [3]. With competitive inhibitors, the familiar S-shaped inhibition curve retains its shape and moves to the right on the dose-scale x axis; this pattern shows how much more drug it would take to overcome resistance, yielding the familiar "fold-change" in inhibitory concentration. But with noncompetitive inhibitors like CCR5 antagonists, the inhibition curve loses its S shape and flattens into a plateau.
When this plateau falls below 95%, Pfizer proposed, virus can be considered resistant to the CCR5 antagonist. Raising the dose, Kutizkes noted, will not overcome this type of resistance. His studies of vicriviroc showed that higher doses of this CCR5 antagonist made resistant virus replicate better. This counterintuitive finding makes sense, he elaborated, because virus resistant to CCR5 antagonists prefers to use drug-bound coreceptors rather than free coreceptors--and raising the dose results in more drug-bound coreceptors.
As Mori's findings confirm, CCR5 antagonist research so far shows that this type "true resistance" explains a minority of failures with this drug. But what explains why HIV becomes resistant to the drug? The Pfizer team found that 9 of 15 people (60%) with maraviroc-resistant virus had no active drugs in their background regimen, so they were essentially taking maraviroc monotherapy. All 15 people with resistant virus had changes in their V3 loop sequences (in the HIV envelope gene) that evolved during failure. But Mori could discern no pattern in these mutations. As Kuritzkes said in his overview talk, research has yet to identify "canonical" mutations that consistently confer resistance to CCR5 antagonists [3]. So at this point genotyping will not predict which viruses may be susceptible to CCR5 blockers.
Of the 21 people without MPI evidence of resistance to maraviroc, 8 (38%) had undetectable maraviroc levels and 7 (33%) had low maraviroc levels--likely signals of poor adherence. Another 2 people had only one sample available for drug-level monitoring.
References
1. Mori J, Lewis M, Simpson P, et al. Characterization of maraviroc resistance in patients failing treatment with CCR5-tropic virus in MOTIVATE 1 and MOTIVATE
2 (24 week analysis). European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 51.
2. 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 Ther. 2007;12:S12.
3. Kuritzkes DJ. Resistance to HIV-1 entry inhibitors. European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Invited lecture.
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