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How Dangerous Is CCR5 Antagonist Failure?
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XVI International HIV Drug Resistance Workshop
June 12-16, 2007
Barbados
Mark Mascolini
Is failure of a CCR5 antagonist regimen riskier than failure of earlier regimens that first used new antiretroviral classes?
That choice question emerged as the chewiest bone of contention at the HIV Resistance Workshop, with several top-drawer clinical investigators, basic researchers, and industry experts lining up on different sides of the dividing line. Industry mavens argued that CCR5 antagonists are being held to a higher standard when judging the impact of their failure, while several academics maintained these drugs should be held to a higher standard because CCR5 antagonists differ in critical ways from nucleosides, nonnucleosides, and protease inhibitors.
The debate took flight when John Mellors (University of Pittsburgh) applauded CCR5 drug developers for painstaking work in describing how HIV may change its colors to escape control by this new class. But he pleaded for more research on defining how often resistance to CCR5 drugs will happen and what level of resistance will put patients at risk of possible disease progression through emergence of virus that prefers the second coreceptor on CD4 cells, CXCR4. Ample research shows that growth of a CXCR4-using viral population portends a more rapid CD4 decline.
Mike Westby of Pfizer, developer of maraviroc, replied that answers to Mellors' questions will come only when research can move beyond the patient subsets analyzed so far and delve for correlates of resistance and response in larger populations.
Chris Petropoulos from Monogram, which makes the main assay that figures coreceptor preference, floated the hypothesis that CCR5 antagonists are being held to a higher standard than other once-novel antiretroviral classes or drugs. After many a year, he maintained, we still don't know exactly how many M184V mutations in a population are enough to touch off high-level resistance to 3TC, and how many K103Ns are enough to take down efavirenz. We won't have similar answers about CCR5 antagonists, Petropoulos cautioned, for at least several years.
Indeed, sundry Resistance Workshop studies spouted copious evidence that HIV can take multiple mutation routes to resistance [1-3]. In fact, mutations do not always correlate with drops in viral susceptibility to CCR5 antagonists [2]. (Other NATAP reports being filed from the workshop detail results of these studies.)
But Mellors insisted resistance to reverse transcriptase or protease inhibitors is "completely different" from resistance to CCR5 antagonists. The reason, he explained, is that no research suggests evolution of M184V or K103N affects the natural history of HIV infection. But resistance to CCR5 antagonists may mean CXCR4 virus gains ground on CCR5 variants, and CXCR4 turns up only in advanced HIV infection. In fact, viral swarms that use both coreceptors apparently threaten CD4s more than strictly CXCR4 virus or strictly CCR5 virus [4], a finding leading Tom Melby of Trimeris to ask, "does it take two to tangle?" [5].
Although Michael Greenberg (Trimeris) and John Coffin (National Cancer Institute) leant their heft to the proposition that Mellors set the bar too high for CCR5 drugs, Robert Shafer (Stanford University) took Mellors' side. When physicians used an earlier new class properly--with other still-active drugs--they could expect the new drug to work, Shafer suggested. But the same may not prove true for CCR5 antagonists because they may open the door to CXCR4 virus already lurking below detection limits. And if a CCR5-based regimen fails, it could short-circuit other drugs in the regimen. Still, Shafer agreed that CCR5 antagonists represent a powerful new class that should be tried in appropriate patients.
Coffin maintained that the pathogenicity of CXCR4 virus remains to be defined. He surmised that if CXCR4 virus makes up only 1% of a viral population, CCR5 antagonists will work. And Anne-Mieke Vandamme (Rega Institute) proposed if a patient candidate for CCR5 antagonist therapy harbors traces of CXCR4 virus, clinicians might think of the CCR5 drug as one with a low barrier to resistance. Mellors retorted that a "no-barrier to resistance" may be a better way to think of it.
Daniel Kuritzkes (Brigham and Women's Hospital) suggested that clinical trials of CCR5 antagonists make one thing clear so far: Most treatment failures involve a flare in the CXCR4 population, because some smidgen of CXCR4 virus--perhaps less than any assay will ever spot--probably hides in covert lairs before the patient ever swallows a CCR5 drug. Kuritzkes said his concern is not the virulence of CXCR4 virus but what happens to other drugs in a regimen if a CCR5 drug fails. Ongoing trials of CCR5 antagonists, he urged, should keep close tabs on how HIV may evolve to thwart other drugs in the salvage regimen if the CCR5-plugging component falters.
Victoria Johnson (University of Alabama) offered one solution to this quandary that everyone could probably agree on: The best bet for a companion drug in a CCR5 antagonist regimen may be a CXCR4 antagonist. But X4 inhibitors lag their R5 cousins on the development trail.
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. 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.
3. 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.
4. Wilkin TJ, Su Z, Kuritzkes DR, et al. HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. Clin Infect Dis. 2007;44:591-595.
5. Melby T. HIV coreceptor use in heavily treatment-experienced patients: does it take two to tangle? Clin Infect Dis. 2007;44:596-598.
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