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Viral Tropism - CCR5 and the Trophile

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Testing for HIV Viral Tropism & Use of CCR5 coreceptor inhibitor Maraviroc

The expression of the chemokine co-receptors CCR5 or CXCR4 on a cell determines whether it can be infected with R5 or X4 using HIV virual strain respectively. Tropism refers to which co-receptor HIV uses to enter a CD4 cell. Dual-tropic viruses can use either CCR5 or CXCR4 co-receptors. Mixed-tropism refers to a viral population that contains both CCR5 or CXCR4 using viral strains.. The current tropism assay cannot differentiate dual-tropic from mixed-tropic, thus the term “dual-mixed” (D/M) virus has emerged.

  • R5-only virus usually predominates early in HIV disease (higher CD4 counts, slower disease progression) while X4 virus often marks more advanced disease. Whether this is a causal association or bystander phenomenon remains controversial.
  • HIV tropism varies depending on antiretroviral exposure and likely reflects the more advanced disease stage of treatment experienced patients :
    • Antiretroviral-naïve: 80-90% R5-only virus, remainder D/M or X4
    • Antiretroviral treatment-experienced: 50-60% R5-only virus, remainder D/M or X4.
  • Currently, only one test commercially available & CLIA-approved to test for HIV viral tropism, a phenotypic assay, Trofile, by Monogram Biosciences
    • Requires HIV RNA level of >1000 copies/mL
    • Turnaround time ~2-3 weeks (it is a sendout to Monogram via Mayo)
    • Not completely sensitive for minority variants:
      • Can detect X4 virus with 100% accuracy when X4 makes up
        ≥ 10% of viral population
      • Detects X4 virus 83% of time when it makes up ≥ 5% of viral population
      • Up to 10% of ARV-treatment experienced patients in clinical trials with initially R5 only virus had D/M on repeat testing 2 weeks later
    • How to order the test at Madison Clinic:
      • Write in “CCR5 assay or Trofile” on routing/order form
      • Assist RNs in completing Monogram form (asks for recent HIV RNA, CD4, provider signature)
      • For your patients with NO insurance, have case manager or Jean Aarvig assist in contacting Monogram to see if patient is eligible for assistance program
    • Test costs nearly $2000

Maraviroc (MVC, Selzentry, Pfizer) is the first chemokine coreceptor antagonist to be FDA approved (August 2007). It is designed to prevent HIV infection of CD4 cells by blocking CCR5.

    • MVC indicated for patients with:
      1. Detectable R5 virus only,
      2. Evidence of viral replication (HIV RNA >1000 copies/mL) and
      3. Resistance to multiple antiretroviral agents
    • Use of MVC is not recommended in patients with D/M or X4 HIV-1, as efficacy not demonstrated in a phase II study in this patient group
    • Safety and efficacy of MVC not established in treatment-naïve adult patients or pediatric patients