FAQs about BCO - CCO2
Why BCO - CCO2 in 3TC, NFV and ETR only?
Why BCO-CCO2 for ETR and BCO only for other NNRTIs?
What is the difference between "susceptible" and "maximal response"?
Is the BCO is appropriate for the treatment-exposed, heavily mutated virus?
For most drugs, Virco uses two Clinical Cut-Offs (CCOs) as the basis for interpretation of resistance. For a number of drugs, the CCO1 (FC associated with 20% loss of drug activity) is actually below the BCO. For three drugs (lamivudine, etravirine, and nelfinavir) an unexpectedly high number of samples with no evidence of exposure to ARV drugs have FC levels slightly above CCO1, leading to a "Reduced Response" resistance interpretation. Although we have demonstrated that the CCOs provide accurate and consistent interpretations of resistance in drug-experienced patients for these drugs, there is currently no clinical evidence to suggest that the response to any of these drugs in treatment naïve patients is compromised by such modest alterations in susceptibility. In order to increase the accuracy of the vircoTYPE report for naive patients, Virco has initiated the following changes to our report as from December 8, 2008, assay version 4.3.00:
On page 1 on the report, we will change the basis of the resistance interpretation for lamivudine, etravirine, and nelfinavir. All samples with FC less than or equal to the BCO will be classified as "Susceptible", viruses with FC between the BCO and CCO2 will be classified as "Reduced Response", and viruses with FC>CCO2 will be classified as "Minimal Response". For samples with FC
On page two of the report Virco will again use the BCO in place of the CCO1 in the drug specific bar graphs for etravirine, nelfinavir, and lamivudine, but will additionally list the BCO values in italics and both the lower and upper CCOs next to each of these drugs. The biological cut-off indicates whether the calculated FC test result is within or above the range of FC values observed with wild type virus.
Why BCO - CCO2 in 3TC, NFV and ETR only?
For 3TC, NFV and ETR, we have seen that a relatively high proportion of viruses with no evidence of exposure to antiretroviral drugs from our genotype database have FC above the CCO1 but below the BCO. While there are other drugs where this occurs, the percentage of such samples affected is below 2.5%, indicating that there is an overlap in distribution of fold change values in naïves and treatment experienced patients.
Why BCO-CCO2 for ETR and BCO only for other NNRTIs?
The use of the BCO for ETR has been implemented to allow a better comparison of ETR resistance with resistance to the other NNRTIs. Because ETR is the first NNRTI to demonstrate significant efficacy in the face of pre-existing NNRTI resistance, it is possible to establish a resistance continuum by determining FC values associated with different degrees of response, providing clinicians with more useful information that can be taken into account when making treatment decisions.
Virco has also calculated two clinical cut-offs based on responses in treatment experienced patients using the same methodology with which Virco has established CCO's for other drugs. These values are represented on page two of the report and can be used as reference points in the resistance continuum. For other NNRTI's, it is very difficult to establish a resistance continuum as they are not used when one of them has failed, therefore, resistance classification for those NNRTI's (nevirapine and efavirenz) is based only on one value (the BCO).
What is the difference between "susceptible" and "maximal response"?
The "susceptible" call indicates that substantial in vitro antiviral activity is retained because the FC for this virus is within the normal susceptibility range for wild-type viruses. A "maximal response" interpretation indicating that substantial in vivo activity of the drug remains. The use of a BCO based interpretation for viruses that exhibit a FC below the BCO (including between CCO1 and BCO) represents a pragmatic approach and does not have a detrimental impact in diagnostic accuracy in treatment experienced patients.
Is the BCO is appropriate for the treatment-exposed, heavily mutated virus?
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