European guidance published on the use of tropism tests in routine HIV care

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Detailed European guidance about the use of tropism testing in routine HIV care has been published in Lancet Infectious Diseases.

The consensus statement was drawn up by 60 panellists from 31 countries.

“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,” write the authors.

Glossary

tropism

When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

CCR5

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

sensitivity

When using a diagnostic test, the probability that a person who does have a medical condition will receive the correct test result (i.e. positive). 

European Medicines Agency (EMA)

Regulatory agency that evaluates medicines for safety and efficacy in Europe, performing a similar role to the Food and Drug Administration (FDA) in the United States. The EMA recommends to the European Commission that a medicine can be marketed in the European Union and European Economic Area.

Viral tropism is the ability of viruses to enter and infect cells, and is based on the ability of viruses to bind to co-receptors on these cells.

HIV uses one of two co-receptors – CCR5 or CXCR4. In most cases, the virus uses CCR5, but CXCR4 virus is found in patients with a low CD4 cell count and in those with extensive experience of HIV treatment.

An antiretroviral drug that targets HIV’s attachment to the CCR5 co-receptor is maraviroc (Celsentri). In both Europe and the US, the drug is approved for use of combination HIV therapy by treatment-experienced patients. In the US, but not Europe, it is also licensed for the treatment of antiretroviral-naïve individuals.

However, maraviroc only works if a patient has HIV that uses the CCR5 co-receptor. Therefore, patients must have a tropism test to assess their suitability for treatment with maraviroc.

Guidelines for the use and interpretation of tropism tests are therefore needed. Investigators reviewed the results of 57 published papers and 42 conference abstracts on the use of tropism tests.

All recommendations had the agreement of 75% of the panel, and the strength of the recommendations was graded as strong, moderate and optional.

The panel strongly recommended that a tropism test should be performed in all circumstances before a patient initiated CCR5 inhibitor therapy. Testing was strongly endorsed for individuals for whom a CCR5 inhibitor was being considered after virologic failure with an earlier regimen.

Patients starting HIV therapy for the first time could have a tropism test before initiating therapy if they are considered to have a high risk of side-effects using conventional first-line anti-HIV drugs. The panel recommend that tests should be conducted as soon as possible before treatment is started, but note, “the use of maraviroc in antiretroviral-naïve patients is not approved by the EMA [European Medicines Agency].”

Also contained in the guidelines are recommendations about the type of tropism test to be used. The choice depends on the viral load of a patient.

For patients with a viral load above 1000 copies/ml, tropism testing using either the enhanced sensitivity Trofile assay or V3 loop genetic population analysis received an endorsement of moderate strength

“The choice of the test should be based on the local capacity, logistics, cost and desired turnaround time,” write the panel.

However, they add, “in general, V3 loop population sequencing is preferred because of its better availability and faster turnaround time. If this method is used, the laboratory should have appropriate expertise in sequencing analysis and use of interpretation techniques and should participate in quality control procedure to validate their accuracy.”

The preferred method of analysis for patients with a viral load between 50 – 1000 copies/ml is the V3 loop. However, the strength of the recommendation was weak.

For patients with an undetectable viral load tropism testing should be done on proviral DNA. Once again, the strength of the recommendation was weak, or optional.

Also in the guidelines are recommendations about the turnaround times for testing.

The importance of speed was emphasised for patients who were possible candidates for CCR5 therapy because of virologic failure. The panel strongly recommended that tropism testing should be performed at the same time as resistance surveillance. “New regimens can therefore be started immediately, avoiding the continuation of failing treatment and associated risk of the accumulation of drug resistance mutations while the tropism test results are awaited.”

Lack of published data prevented the panel from making recommendations about the longevity of test results. However, they suggested that the risk of tropism change was low for patients with higher CD4 cell counts. But the investigators emphasised the need for short turnaround times for individuals with a low CD4 cell count, as well as those taking a failing regimen. “In this case,” they write, “genotypic assays using population sequencing are preferable to phenotypic assays.”

The test report sent by laboratories to doctors should, the guidelines stress, “include clear advice as to whether the tropism result supports the use of a CCR5 antagonist or not.” The guidance also states that the laboratory report should indicate which type of test was used, and that “virologists providing the results should have knowledge of the association between sensitivity and specificity of tropism prediction and cutoff settings.”

The guidelines conclude, “current data lend support to both the use of population genotyping and the commercially available enhanced sensitivity Trofile assay…for practical reasons, genotypic population sequencing is the preferred method in Europe.”

References

Vandekerckhove LPR et al. European guidelines on the clinical management of HIV-1 tropism testing. Lancet Infectious Diseases, online advance publication, March 22, 2011. (click here for access to the free abstract).