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HIV-1 Coreceptor Tropism, Proviral DNA

HIV-1 Coreceptor Tropism, Proviral DNA

Test Summary

HIV-1 Coreceptor Tropism, Proviral DNA

  

Clinical Use

  • Determine eligibility for CCR5 antagonist therapy in HIV-1-infected patients with a viral load <1,000 HIV RNA copies/mL

Clinical Background

Entry inhibitors, the newest class of antiretroviral drugs for HIV-1 infection, target the process by which HIV-1 enters the host cell. This viral entry 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. 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

Maraviroc (MVC; Selzentry®) was one of the first entry inhibitors 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 dual/mixed-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 antagonist.4

Genotypic and phenotypic HIV-1 coreceptor tropism testing requires adequate levels of HIV-1 RNA (typically ≥1,000 copies/mL). Because successful antiretroviral therapy can suppress HIV-1 RNA to well below this level, patients receiving suppressive therapy may not have enough RNA for tropism to be determined. One option in such cases is to test HIV-1 proviral DNA in whole blood or PBMCs.

Proviral HIV-1 DNA refers to HIV-1 DNA that has integrated into the host genome of infected T-lymphocytes. Because proviral DNA persists despite suppressive therapy, it can be used to determine tropism status when HIV-1 RNA is undetectable.5 Although X4 sequences are more commonly found in proviral DNA than RNA, several studies have found a high degree of concordance between proviral DNA and RNA tropism predictions.5-7 Proviral DNA sequence analysis thus provides an attractive route to determine tropism status for patients considering a switch to an MVC-containing regimen (eg, to simplify or intensify a regimen) while still fully suppressed.5 Although current US guidelines indicate that proviral testing can be used to determine tropism in patients with undetectable viral load, they note that the clinical utility of this approach has not yet been determined.4

This test is for patients with a viral load <1,000 HIV RNA copies/mL. For patients with a viral load ≥1,000 HIV-1 copies/mL, refer to test code 90666(X), HIV-1 Coreceptor Tropism with Reflex to Ultradeep Sequencing.

Individuals Suitable for Testing

  • HIV-1-infected patients with a viral load <1,000 copies/mL who are being considered for treatment with CCR5 antagonist therapy

Method

  • DNA extraction

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

  • Triplicate Sanger DNA sequencing of codons 1-35 of the V3 loop and bioinformatic analysis

  • Results reported:

   CXCR4 (X4): detected or not detected

–   Net tropism assessment: R5 or DM/X4

 –  MVC activity anticipated: yes or no

  • Sensitivity

   Technical: limit of detection (LOD95): 480 DNA copies/mL (whole blood)

–   Analytical (biological): LOD95 in dual/mixed mimicked clinical samples is 20%

  • 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.

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

Reference Range

CXCR4 (X4) not detected

Interpretive Information

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

Individuals infected with X4-tropic or dual/mixed-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) tablets [prescribing information]. Research Triangle Park, NC:ViiV Healthcare; July 2011. Available at: http://www.viivhealthcare.com/products/~/media/Files/G/GlaxoSmithKline-Plc/Attachments/
    pdfs/products/us_selzentry_jul2011.pdf. Accessed February 23, 2012.

  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. March 27, 2012. Available at:
    http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed September 13, 2012.

  5. Vandekerckhove LP, Wensing AM, Kaiser R, et al. European guidelines on the clinical management of HIV-1 tropism testing. Lancet Infect Dis. 2011;11:394-407.

  6. Seclen E, Del Mar GM, De MC, et al. Dynamics of HIV tropism under suppressive antiretroviral therapy: implications for tropism testing in subjects with undetectable viraemia. J Antimicrob Chemother. 2010;65:1493-1496.

  7. Verhofstede C, Brudney D, Reynaerts J, et al. Concordance between HIV-1 genotypic coreceptor tropism predictions based on plasma RNA and proviral DNA. HIV Med. 2011;12:544-552.

  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 performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.
 Content reviewed 12/2012
 

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