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Mutations Don't Explain Vicriviroc Failure in ACTG Trial
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XVI International HIV Drug Resistance Workshop
June 12-16, 2007
Barbados
Mark Mascolini
Mutations in the V3 loop of HIV's env gene arose in 5 of 9 people in whom the CCR5 antagonist vicriviroc failed in AIDS Clinical Trials Group (ACTG) study 5211 [1]. But those mutations did not reduce viral susceptibility to vicriviroc, a result indicating that some other mechanism explains vicriviroc failure.
ACTG investigators analyzed virus from 8 randomly selected people whose vicriviroc-based salvage regimen failed by week 16 of the study, including 2 each from the placebo group and the 5-, 10-, and 15-mg vicriviroc groups. They also scrutinized viral samples from 1 person in whom phenotyping showed progressive loss of viral susceptibility to the CCR5 blocker.
No V3 loop mutations evolved in the 4 people taking placebo or 15 mg of vicriviroc daily. Mutations did develop in all 4 people taking 5 or 10 mg of vicriviroc. These mutations arose at different V3 loop sites in each of the 4 viral samples studied and became fixed in the viral population after virologic failure. But the clinical meaning of these mutations remains uncertain because they did not correlate with decreases susceptibility to vicriviroc measured as either change in 50% inhibitory concentration of percent change in maximal suppression.
Nor did viral susceptibility to vicriviroc change in the 2 people whose vicriviroc regimen faltered without emergence of mutations. In all 8 randomly selected people with virologic failure, maximum fold change in susceptibility to vicriviroc measured only 2.83. Sequential viral samples from the one person who did have phenotypic evidence of resistance to vicriviroc also showed multiple V3 loop mutations.
This lack of consistency in which mutations arise in people taking vicriviroc probably reflects the high diversity of HIV's envelope sequence. Years of research already shows env is malleable enough to evade antibody control, not to mention human-made vaccines.
Testing trial participants' virus for coreceptor preference showed only CCR5-favoring virus in all 9 of these individuals when the study began. Repeat testing after virologic failure demonstrated that some viruses in each person's viral population could now infect CXCR4-favoring virus. Although the viral populations of these people remained largely CCR5-favoring, emergence of CXCR4 virus seems a more likely explanation of treatment failure than env mutations. Research consistently links emergence of CXCR4-using variants with worsening HIV infection, but it remains unclear whether the CXCR4-leaning virus contributes to disease progression or merely signals progression.
In the one person with phenotypic evidence of resistance to vicriviroc, a viral sample taken 5 months after vicriviroc therapy stopped demonstrated a return of viral susceptibility to the drug, re-emergence of a CCR5-only viral population, and gradual disappearance of the V3 mutations. Those changes led the ACTG team to propose that nonmutant virus has a fitness advantage over mutant virus (meaning it replicates better than mutant virus).
Evidence from this study also implies that resistant HIV doesn't care if a CCR5 antagonist is already plugging a CCR5 receptor--it will use that receptor anyway. Tsibris's experiments using env clones derived from people in whom vicriviroc failed showed a plateau in vicriviroc susceptibility--evidence Tsibris interpreted as "suggesting improved efficiency of viral entry using vicriviroc-bound CCR5." By week 2 of vicriviroc treatment in these people, "enhanced viral growth in the presence of vicriviroc further suggests that HIV-1 had adapted preferentially to enter target cells more efficiently using vicriviroc-bound CCR5 than native CCR5."
Meanwhile, a study by Monogram Biosciences found that mutations outside the V3 loop can further resistance to CCR5 antagonists [2]. In fact, the Monogram team argued that high-level resistance to CCR5 antagonists may depend on multiple mutations outside of V3. But Pfizer work on maraviroc suggested V3 mutations are both necessary and sufficient for resistance to CCR5 antagonists [3]. NATAP will provide separate reports of these studies.
References
1. 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.
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. 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.
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