CCR5 Tropism testing for Maraviroc
Genetics of Maraviroc Response
The human immunodeficiency virus (HIV) replicates itself in humans by infecting T cells with CD4 receptors (often called CD4 cells). HIV enters the CD4 cell by binding to one of two cell surface co-receptors: CCR5 or CXCR4.1, 2
Tropism refers to the ability of HIV virus to use one or both of these co-receptors. There are three main tropism classifications:3
- CCR5 tropism (also called R5-tropic): HIV virus that only infects cells with the CCR5 co-receptor.
- CXCR4 tropism (also called X4-tropic): HIV virus that only infects cells with the CXCR4 co-receptor.
- Dual or mixed tropism: HIV virus populations that can use either co-receptor to infect cells.
The tropism classification frequently changes over the course of the disease. CCR5-tropic virus predominates in early infection and treatment naïve patients.1-3 CXCR4 tropism increases both as the disease progresses and with treatment.1 In later infection, CXCR4 tropism emerges in about 20% of treatment naïve patients.3 Treatment experienced patients have up to a 50% chance for the presence of CXCR4-tropic virus.1
Maraviroc (Selzentry®) is an antiretroviral drug that selectively binds to the CCR5 co-receptor. This blocks CCR5-tropic HIV from binding to the co-receptor and entering the cell.4 Maraviroc is effective only against CCR5-tropic HIV. Patients with viruses using both the CXCR4 and CCR5 receptors (dual/mixed tropic) did not respond virologically to maraviroc.4, 5 Therefore, maraviroc is not indicated for CXCR4-tropic or dual/mixed HIV.4 Outgrowth of undetected CXCR4 virus present before maraviroc treatment is initiated can result in virologic failure on maraviroc.4
Use and Test Details
HIV tropism testing:
- Should be performed before maraviroc therapy is initiated. Maraviroc should only be used in adults with CCR5-tropic HIV, based on those results.2, 4
- May also be considered for patients with maraviroc treatment failure. Treatment failure is often associated with a switch to CXCR4 tropism.6
Phenotypic testing was the first HIV tropism assay available, was the exclusive test used in maraviroc clinical trials, and is most widely recommended.2, 7-10 The Trofile website states that the assay is "100% sensitive at detecting 0.3% CXR4 using minor variant."9
HIV tropism phenotype testing is performed through Medco's lab partner using the CCR5 tropism test. Results are shared back with the patient's physician. Once testing is ordered, a test kit is sent to the patient to take to a local site for blood draw. Testing is offered to patients whose employers or health plans have enrolled their members in the Medco personalized medicine program. The program is offered at no cost to eligible members and their physicians. If you are not sure a patient is eligible for Medco's personalized medicine program for Maraviroc, please contact a Medco representative at 1 800 838-5233, between 9:00 a.m. and 5:30 p.m., eastern time, Monday through Friday.
Label and Recommendations
Maraviroc (Selzentry) has been approved for use in treatment-experienced adults with only CCR5-tropic HIV-1 virus and evidence of replication, despite the use of several other antiretroviral therapies.4 Regarding tropism testing, maraviroc product labeling states that:4
- "Tropism testing must be conducted with a highly sensitive tropism assay that has demonstrated the ability to identify patients appropriate for SELZENTRY use."
- "Use of SELZENTRY is not recommended in subjects with dual/mixed or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a phase 2 study of this patient group."
A Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents recommends: 2
- "Coreceptor tropism assay should be performed whenever the use of a CCR5 inhibitor is being considered (AII)."
- "Coreceptor tropism testing might also be considered for patients who exhibit virologic failure on a CCR5 inhibitor (BIII)."
Infectious Diseases Society of America guidelines agree that tropism testing should be done before starting any CCR5 antagonist.10 These guidelines do not address testing based on treatment failure.
Impact on Treatment Decisions
If the results identify CCR5-tropic virus, maraviroc therapy is reasonable.2 These results do not predict adverse reactions to maraviroc. Normal monitoring for safety and efficacy is still required.4
If the results identify CXCR4- or dual/mixed-tropic virus, maraviroc therapy should not be used. If therapy was already started, it should be discontinued in favor of another antiretroviral.2 Evidence shows that maraviroc is not effective at preventing cell entry of virus that can use the CXCR4 co-receptor.4
- Yost R, Pasquale TR, Sahloff EG. Maraviroc: a coreceptor CCR5 antagonist for management of HIV infection. Am J Health Syst Pharm. Apr 15 2009;66(8):715-726.
- 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. December 1, 2009; 1-161. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.† Accessed November 5, 2010.
- Simon B, Grabmeier-Pfistershammer K, Rieger A, Sarcletti M, Schmied B, Puchhammer-Stockl E. HIV coreceptor tropism in antiretroviral treatment-naive patients newly diagnosed at a late stage of HIV infection. AIDS. Aug 24 2010;24(13):2051-2058.
- US Food and Drug Administration. Selzentry (maraviroc) tablets label. 2010; http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022128s004lbl.pdf.† Accessed November 5, 2010.
- Pfizer Inc. Maraviroc Tablets NDA 22-128: Antiviral drugs advisory committee briefing document. 2007; http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4283b1-01-Pfizer.pdf.†
- Armand-Ugon M, Moncunill G, Gonzalez E, et al. Different selection patterns of resistance and cross-resistance to HIV-1 agents targeting CCR5. J Antimicrob Chemother. Mar 2010;65(3):417-424.
- McCarthy MC, Vilchez R, Quiroz J, Strizki J, Liberi J, Dunkle LM. Comparison of Phenotypic (Trofile.) and Genotypic (SensiTrop II) Assays to Determine HIV Tropism in Treatment-naïve Subjects. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Canada2009.
- Recordon-Pinson P, Soulie C, Flandre P, et al. Evaluation of the genotypic prediction of HIV-1 coreceptor use versus a phenotypic assay and correlation with the virological response to maraviroc: the ANRS GenoTropism study. Antimicrob Agents Chemother. Aug 2010;54(8):3335-3340.
- Monogram Biosciences Inc. What Is Trofile. 2009; http://www.trofileassay.com/what_is_trofile.html.† Accessed November 5, 2010.
- Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. Sep 1 2009;49(5):651-681.