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HIV-1 Coreceptor Tropism, Ultradeep Sequencing

HIV-1 Coreceptor Tropism, Ultradeep Sequencing

Test Summary

HIV-1 Coreceptor Tropism, Ultradeep Sequencing

  

Clinical Use

  • Guide selection of antiretroviral drugs

  • Determine eligibility for CCR5 antagonist therapy in patients infected with human immunodeficiency virus 1 (HIV-1)

Clinical Background

Numerous antiretroviral drugs belonging to different classes are available to treat HIV-1 infection. Entry inhibitors target the process by which HIV-1 enters the host cell. This process requires the use of the CD4 receptor and 1 of 2 chemokine coreceptors, CCR5 or CXCR4, located on the host cell surface membrane. HIV-1 virions that use CCR5 are called R5-tropic and those using CXCR4 are called X4-tropic. Viral mixtures using both coreceptors are called dual or mixed-tropic (DM). R5-tropic viruses are more common in treatment-naive patients. In contrast, X4- tropic viruses are found in only about 13% of recent seroconverters1 but in up to 50% of treatment-experienced patients and those with advanced disease.2

Selzentry® (maraviroc [MVC]) is the first CCR5 antagonist to obtain FDA approval. MVC binds to the CCR5 coreceptor, thereby inhibiting coreceptor binding of R5-tropic HIV-1 virions. Clinical trials using a phenotypic assay to determine HIV-1 tropism showed that MVC is not effective against X4 or DM-tropic HIV-1.3 Thus, tropism testing should be performed before initiating MVC therapy and may also be considered for patients who exhibit virologic failure while taking a CCR5 inhibitor.4 Both phenotypic and genotypic tropism testing are clinically available. Although phenotypic tropism testing is generally preferred because of a greater weight of supporting evidence, genotypic tropism testing is considered an alternative because of its lower cost and faster analytical times.4

The Quest Diagnostics HIV-1 coreceptor tropism test uses ultradeep sequencing (UDS) technology. UDS performance is comparable to phenotypic tropism tests for predicting clinical response to MVC therapy.5,6 The positive and negative predictive values of the Quest Diagnostics test for distinguishing virologic responders from nonresponders are similar to those of a high-sensitivity phenotypic test.7

Individuals Suitable for Testing

  • Patients being considered for treatment with maraviroc

  • Patients who exhibit virologic failure while taking maraviroc

Method

  • Reverse transcription and PCR amplification of the HIV-1 envelope V3 loop in triplicate

  • Ultradeep sequencing of codons 1-35 of the V3 loop and bioinformatic analysis

  • Sensitivity

    –  Technical: limit of detection (LOD95) of UDS instrument is 0.5% X4.7

    –  Analytical (biological): LOD95 of UDS assay in DM-mimicked clinical samples is 18% X4 virus at 25,000 copies/mL and 6% X4 virus at 100,000 copies/mL.7

  • HIV-1 subtype specificity: HIV-1 subtypes A, B, C, D, AG, and H are successfully amplified, but subtypes AE, F, and G are not.

  • Results reported:

    –  CXCR4 (X4): detected or not detected

    –  Tropism assessment: R5 or DM/X4

    –  MVC activity anticipated: yes or no

  • Aliases: human immunodeficiency virus, CCR5, CXCR4, R5, X4

Interpretive Information

MVC is not recommended for patients infected with X4- or DM-tropic HIV-1.3 Thus, alternative therapy should be considered if the net tropism assessment result is "X4" or "DM/X4." A net tropism assessment of "R5" is consistent with eligibility for treatment with a CCR5 antagonist.

Individuals infected with X4- or DM-tropic HIV-1 are more likely to have a lower CD4 cell count, higher viral load, and more rapid progression to AIDS than individuals without an X4-tropic population.8,9

Because fewer tropism data are available for non-B subtypes, tropism determination for these subtypes may have a greater degree of uncertainty.

References

  1. Poveda E, Briz V, de Mendoza C, et al. Prevalence of X4 tropic HIV-1 variants in patients with differences in disease stage and exposure to antiretroviral therapy. J Med Virol. 2007;79:1040-1046.

  2. Wilkin TJ, Su W, 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.

  3. Selzentry® (maraviroc) tablet, film coated [prescribing information]. Research Triangle Park, NC:ViiV Healthcare; November 2016. https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/
    Prescribing_Information/Selzentry/pdf/SELZENTRY-PI-MG-IFU.PDF
    . Accessed December 14, 2016.

  4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1–infected adults and adolescents. Department of Health and Human Services. http://www.aidsinfo.nih.gov/
    ContentFiles/AdultandAdolescentGL.pdf
    . Updated July 14, 2016. Accessed November 1, 2016.

  5. Swenson LC, Mo T, Dong WW, et al. Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients. J Infect Dis. 2011;203:237-245.

  6. Swenson LC, Mo T, Dong WW, et al. Deep V3 sequencing for HIV type 1 tropism in treatment-naive patients: a reanalysis of the MERIT trial of maraviroc. Clin Infect Dis. 2011:53:732-742.

  7. Kagan RM, Johnson EP, Siaw M, et al. A genotypic test for HIV-1 tropism combining Sanger sequencing with ultradeep sequencing predicts virologic response in treatment-experienced patients. PloS One. 2012;7(9):e46334.

  8. Daar ES, Kesler KL, Petropoulos CJ, et al. Baseline HIV type 1 coreceptor tropism predicts disease progression. Clin Infect Dis. 2007;45:643-649.

  9. Waters L, Mandalia S, Randell P, et al. The impact of HIV tropism on decreases in CD4 cell count, clinical progression, and subsequent response to a first antiretroviral therapy regimen. Clin Infect Dis. 2008;46:1617-1623.
     

This test was developed and its analytical performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by FDA. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes.

Content reviewed 12/2016

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