Review
European guidelines on the clinical management of HIV-1 tropism testing

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Summary

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. Testing for HIV tropism is recommended before prescribing a chemokine receptor blocker. In most European countries, HIV tropism is identified with tropism phenotype testing. New data support genotype analysis of the HIV third hypervariable loop (V3) for the identification of tropism. The European Consensus Group on clinical management of tropism testing was established to make recommendations to clinicians and clinical virologists. The panel recommends HIV-tropism testing for the following groups: drug-naive patients in whom toxic effects are anticipated or for whom few treatment options are available; patients who have poor tolerability to or toxic effects from current treatment or who have CNS pathology; and patients for whom therapy has failed and a change in treatment is considered. In general, an enhanced sensitivity Trofile assay and V3 population genotyping are the recommended methods. Genotypic methods are anticipated to be used more frequently in the clinical setting because of their greater accessibility, lower cost, and faster turnaround time than other methods. For the interpretation of V3 loop genotyping, clinically validated systems should be used when possible. Laboratories doing HIV tropism tests should have adequate quality assurance measures. Similarly, close collaboration between HIV clinicians and virologists is needed to ensure adequate diagnostic and treatment decisions.

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

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