The CCR5 antagonist maraviroc (as well as vicriviroc, an investigational CCR5 antagonist) is active against HIV virus that exclusively uses the CCR5 coreceptor. It is not effective against CXCR4-tropic or dual/mixed-tropic HIV, and using maraviroc in patients with CXCR4 virus can cause virologic failure. Thus, it is important to determine coreceptor tropism before initiating treatment with maraviroc and to use maraviroc only in patients with exclusive CCR5-tropic virus.
Unfortunately, the tropism assays available to date have had suboptimal sensitivity for low-level populations of CXCR4-tropic HIV. In Phase 2b/3 studies of maraviroc, nearly 8% of patients whose tropism assay at the time of screening showed exclusive CCR5-tropic virus were found on retesting with the same assay to have dual or mixed tropism.(1,2) The commercially available coreceptor assay, marketed under the brand name Trofile, is reported by the manufacturer to have a sensitivity of only 85% when CXCR4 virus makes up 5% of the viral population, based on comparison with clonal analysis.
Work to improve the sensitivity of chemokine coreceptor assays has been ongoing, and at the XVII International HIV Drug Resistance Workshop, scientists with Monogram Biosciences, the Trofile manufacturer, presented results from studies of their new assay.(3) Using varying mixtures of CCR5 and CXCR4 clones, the assay was shown to have a sensitivity of 100% for detecting a 0.3% minor population of CXCR4-tropic HIV. Further, 18 patient samples that were inaccurately identified as exclusive CCR5 viral populations by the standard assay (clonal analysis detected CXCR4 variants) were retested with the new assay; 14 of these were correctly identified as containing CXCR4 viruses.
Clinical Bottom Line
This coreceptor tropism assay is significantly more sensitive for the detection of minor populations of CXCR4-tropic HIV. It should improve the ability of clinicians to identify patients who are likely to respond to CCR5 antagonists such as maraviroc. Note that coreceptor testing should be done before treatment with a CCR5 antagonist is initiated, and when the patient's HIV RNA is ≥1,000 copies/mL.
- Nelson M, Fatkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 104aLB.
- Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 104bLB.
- Trinh L, Han D, Huang W, et al. Technical validation of an enhanced sensitivity Trofile HIV co-receptor tropism assay for selecting patients for therapy with entry inhibitors targeting CCR5. In: Program and abstracts of the XVII International HIV Drug Resistance Workshop; June 10-14, 2008; Sitges, Spain.