ReviewEuropean guidelines on the clinical management of HIV-1 tropism testing
Introduction
Viral tropism is the ability of viruses to enter and infect specific host cells and is based on the ability of viruses to bind to receptors on those cells. C-C chemokine receptor type 5 (CCR5) antagonists, such as maraviroc and vicriviroc, specifically inhibit the entry into host cells and subsequent replication of CCR5-tropic HIV variants (R5 virus) by an allosteric mechanism after binding to the transmembrane CCR5 co-receptor cavity. The European Medicines Agency (EMA) has approved maraviroc for use in treatment-experienced adults in whom only CCR5-tropic virus is detected. The US Food and Drug Administration (FDA), but not the EMA, has also approved maraviroc for use in treatment-naive R5-only individuals. Hence, assessment of viral tropism is needed for clinical use of the drug. In registration trials, the original Trofile assay (Monogram Biosciences, San Francisco, CA, USA) was used for this purpose. An enhanced version of the Trofile assay with improved sensitivity for the detection of HIV variants capable of using the chemokine C-X-C-motif receptor 4 (CXCR4 receptor; X4 virus) has now replaced the original Trofile assay. Additionally, several other phenotypic and genotypic approaches for establishing tropism have been developed. As the number of tropism assessment methods increases, guidelines for their use and interpretation are needed. We review published work and summarise the consensus statement of the European Consensus Group on clinical management of tropism testing. The recommendations of the panel comprise clinical indications for tropism testing, selection of the appropriate method to establish tropism, and guidance for the adequate interpretation of results obtained with these methods.
Section snippets
Search strategy and selection criteria
We systematically reviewed published work in accordance with the Quality of Reporting of Meta-analyses (QUOROM) guidelines.1 We searched PubMed for articles published in English from Jan 1, 2006, to March 31, 2010, with the terms “tropism”, “CCR5-antagonist”, “CCR5 antagonist”, “maraviroc”, or “vicriviroc”. Additional articles or abstracts were identified from references in the identified articles. We systematically searched the abstract books from key conferences that were held in the same
Results
57 papers and 42 conference abstracts met our inclusion criteria (figure).
Clinical indications for tropism testing
Before treatment with a CCR5 antagonist is started, co-receptor tropism should be identified (recommendation level AII; table 3). Tropism testing is strongly recommended in all patients who have virological failure for whom a CCR5 antagonist is being considered as part of the subsequent regimen (AII). Tropism testing is moderately recommended in all patients for whom treatment has failed to provide insight into future treatment options (BII).
In patients who have adverse events with their
Conclusions
After the EMA approval of maraviroc, the first CCR5 co-receptor antagonist for the treatment of HIV-1 infection, tropism testing is needed for clinical practice. The European Consensus Group on clinical management of tropism testing provide an overview of available published work, evidence-based recommendations for the clinical use of tropism testing, and guidance on unresolved factors and developments. Current data lend support to both the use of population genotyping and the commercially
References (105)
- et al.
Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses
Lancet
(1999) - et al.
HIV coreceptors: role of structure, posttranslational modifications, and internalization in viral-cell fusion and as targets for entry inhibitors
Biochim Biophys Acta
(2003) - et al.
Development and performance of a new recombinant virus phenotypic entry assay to determine HIV-1 coreceptor usage
J Clin Virol
(2010) - et al.
A genotypic resistance assay for the detection of drug resistance in the human immunodeficiency virus type 1 envelope gene
J Virol Methods
(2005) Adult and Adolescent Guidelines
- et al.
Cell surface receptors, virus entry and tropism of primate lentiviruses
J Gen Virol
(2002) - et al.
The CCR5 and CXCR4 coreceptors—central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection
AIDS Res Hum Retroviruses
(2004) - McGeehan K, Polacchini de Oliveira A, Hoxie J. Effects of HIV-1 variants containing partial deletions within the V3...
- et al.
Effect of major deletions in the V1 and V2 loops of a macrophage-tropic HIV type 1 isolate on viral envelope structure, cell entry, and replication
AIDS Res Hum Retroviruses
(1998) - et al.
Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains
Proc Natl Acad Sci USA
(1997)
HIV and the chemokine system: 10 years later
EMBO J
A new classification for HIV-1
Nature
Structural basis for coreceptor selectivity by the HIV type 1 V3 loop
AIDS Res Hum Retroviruses
Infection of cells expressing CXCR4 mutants lacking N-glycosylation at the N-terminal extracellular domain is enhanced for R5X4-dualtropic human immunodeficiency virus type-1
BMC Infect Dis
Sialylated O-glycans and sulfated tyrosines in the NH2-terminal domain of CC chemokine receptor 5 contribute to high affinity binding of chemokines
J Exp Med
Chemokine antagonists as therapeutics: focus on HIV-1
Annu Rev Med
Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the multicenter AIDS cohort study
J Infect Dis
Prevalence of CCR5-tropic HIV-1 among treatment-experienced individuals in Spain
HIV Clin Trials
CD4-dependent characteristics of coreceptor use and HIV type 1 V3 sequence in a large population of therapy-naive individuals
AIDS Res Hum Retroviruses
Prevalence of X4 tropic HIV-1 variants in patients with differences in disease stage and exposure to antiretroviral therapy
J Med Virol
Characterization of human immunodeficiency virus type 1 populations containing CXCR4-using variants from recently infected individuals
AIDS Res Hum Retroviruses
Performance of a population-based HIV-1 tropism phenotypic assay and correlation with V3 genotypic prediction tools in recent HIV-1 seroconverters
J Acquir Immune Defic Syndr
Presence of HIV-1 R5 viruses in cerebrospinal fluid even in patients harboring R5X4/X4 viruses in plasma
J Acquir Immune Defic Syndr
Mode of coreceptor use by R5 HIV type 1 correlates with disease stage: a study of paired plasma and cerebrospinal fluid isolates
AIDS Res Hum Retroviruses
Evaluation of diagnostic tests for infectious diseases: general principles
Nat Rev Microbiol
Determination of cell tropism of HIV-1
Methods Mol Biol
Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism
Antimicrob Agents Chemother
Response to vicriviroc in treatment-experienced subjects, as determined by an enhanced-sensitivity coreceptor tropism assay: reanalysis of AIDS clinical trials group A5211
J Infect Dis
Design and validation of new genotypic tools for easy and reliable estimation of HIV tropism before using CCR5 antagonists
J Antimicrob Chemother
High sensitivity of specific genotypic tools for detection of X4 variants in antiretroviral-experienced patients suitable to be treated with CCR5 antagonists
J Antimicrob Chemother
Improvement in the determination of HIV-1 tropism using the V3 gene sequence and a combination of bioinformatic tools
J Med Virol
Robust supervised and unsupervised statistical learning for HIV type 1 coreceptor usage analysis
AIDS Res Hum Retroviruses
Comparison of two genotypic algorithms to determine HIV-1 tropism
HIV Med
Determining human immunodeficiency virus coreceptor use in a clinical setting: degree of correlation between two phenotypic assays and a bioinformatic model
J Clin Microbiol
Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo
PLoS One
The Berlin Maraviroc cohort—influence of genotypic tropism testing results on therapeutic outcome. 7th European HIV Drug Resistance Workshop; Stockholm, Sweden; March 27–29, 2009. Abstract 79
Rev Antivir Ther
Genotypic prediction of viral co-receptor tropism: correlation with enhanced Trofile. 7th European HIV Drug Resistance Workshop; Stockholm, Sweden; March 27–29, 2009. Abstract 80
Rev Antivir Ther
Tropism testing from proviral DNA—analysis of a subgroup from the Berlin Maraviroc cohort. 8th European HIV Drug Resistance Workshop; Sorrento, Italy; March 17–19, 2010. Abstract 23
Rev Antivir Ther
Genotypic and phenotypic HIV Tropism testing predicts the outcome of maraviroc regimens
Antivir Ther
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
Use of a genotypic assay for prediction of HIV-1 co-receptor tropism and guiding the use of CCR5 antagonists in clinical practice. 8th European HIV Drug Resistance Workshop; Sorrento, Italy; March 17–19, 2010. Abstract 44
Rev Antivir Ther Infect Dis
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These authors contributed equally to this paper