Clinical Cut-Offs FAQ

• What exactly are clinical cut-offs and why are they important?
• Why are clinical cut-offs better suited to HIV resistance testing than are biological cut-offs?
• Can I apply these new clinical cut-off values to other phenotypic resistance tests?
• If clinical cut-offs represent a more clinically relevant approach to interpreting resistance information, why is Virco still using biological cut-offs for some drugs?
   

What exactly are clinical cut-offs and why are they important?

Clinical cut-offs are a better, clinically-derived (based on responses of real patients treated with ARV drugs), reference values to determine which drugs are no longer active, and which retain partial or full activity when evaluating quantitative fold-change information. Two clinical cut-offs (CCOs) values have been defined: a) a 'lower' value: the point at which virologic response begins to be lost - and b) a 'higher' value: the point at which virologic response is essentially gone.

Compared to so-called 'biological' cut-offs, clinical cut-offs represent a different, more clinically relevant approach to interpreting resistance information, providing a higher degree of correlation with virologic outcomes.

The clinical cut-offs developed for the virco® TYPE HIV-1 test provide physicians with clinically relevant resistance information, allowing them to use the test more effectively in enhancing the utility of currently available antiretroviral treatment (ART) regimens.
 

Why are clinical cut-offs better suited to HIV resistance testing than are biological cut-offs?

In order to understand the value that clinical cut-offs bring to test result interpretation it is important to take a look at previous approaches. Early approaches to evaluating HIV resistance testing data were based on assay reproducibility (technical cut-offs). A second-generation approach, so-called biological cut-offs (BCO) relied on data derived from testing in vitro a large number of viral isolates obtained from naïve patients, in other words patients that have never received antiretroviral therapy. Although clearly better than technical cut-offs, this approach still did not provide a link with virologic responses in vivo.

The use of clinical cut-offs represents a different, more clinically relevant approach to interpreting resistance information. The statistical model from which clinical cut-offs are derived correlates baseline fold-change information (a measure of the increase in a drug's IC50, the concentration of the drug that inhibits 50% of viral replication) for a particular drug with actual virologic response. This information is based on clinical trial and patient cohort data that show a loss in viral suppression in patients with a certain degree of baseline phenotypic resistance to that drug. Additionally, unlike the approach for biological cut-offs, the approach used to determine clinical cut-offs takes into account combination regimens, providing results that are more closely related to actual prescribing patterns. The clinical cut-offs enhance the value of the virco® TYPE HIV-1 test by applying consistent definitions across ART drugs.
 

Can I apply these new clinical cut-off values to other phenotypic resistance tests?

No. The clinical cut-offs developed for the virco® TYPE HIV-1 test are assay-specific and their performance has not been tested with other resistance assays. The virco® TYPE HIV-1 test is the first resistance test that provides phenotypic information and expert clinical knowledge at a fraction of the cost of conventional phenotyping, and the only resistance test to which consistent clinical cut-offs can be applied, thus making the interpretation of results more clinically relevant than is possible with other resistance tests. Additionally, in the future, the Virco will continue to update and refine assay-specific clinical cut-offs for current and new drugs, allowing for optimal interpretation of phenotypic resistance.
 

If clinical cut-offs represent a more clinically relevant approach to interpreting resistance information, why is Virco still using biological cut-offs for some drugs?

There are some drugs for which there is insufficient clinical data to establish clinical cut-offs. For those drugs, biological cut-offs are still the best reference values for interpreting resistance information. That said, we continue to collect clinical data with the aim of deriving clinical cut-offs for all antiretroviral drugs.