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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)
    • First generation assay was not completely sensitive for minority variants, but new generation “enhanced sensitivity” Trofile assay can detect X4 virus to levels less than 0.3% of viral population.
  • 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

References

Trinh, L, Han, D, Huang, W, et al. Technical validation of an enhanced sensitivity Trofile HIV coreceptor tropism assay for selecting patients for therapy with entry inhibitors targeting CCR5. Antiviral therapy 2008; 13 Suppl 3:A128.