Etravine Resistance FAQ

• I see a vircoTYPE report with no NNRTI mutations listed on page one, and yet there is a "reduced response" prediction for etravirine. Why?
• Why do I see a "reduced response" prediction for etravirine but a "susceptible" prediction for efavirenz and/or nevirapine?
• Why is your CCO1 for ETR below the BCO?
   

I see a vircoTYPE report with no NNRTI mutations listed on page one, and yet there is a "reduced response" prediction for etravirine. Why?

Page 1 of the vircoTYPE report lists selected mutations commonly accepted as being associated with drug resistance, as reported on three publicly-available lists, IAS-USA, Stanford and ANRS France or as reported by pharmaceutical sponsors. These "commonly accepted" mutation lists may not include rare or newly emerging mutations or certain mutations whose impact on the FC is modest.

In some cases, the virtual Phenotype-LM calculated FC for a sample is above CCO1, resulting in a "reduced response" call, without any of these commonly recognized mutations being detected in the sample. The list of all mutations detected (pg 2 of the report) always includes the mutations considered by virtual Phenotype-LM in calculating FC for each drug. Because the virtual Phenotype-LM was developed to accurately calculate the phenotype (FC), it can evaluate the impact of any mutation - strong mutations but also mutations with a lesser impact- and incorporate this information into the FC calculation for incoming samples.
 

Why do I see a "reduced response" prediction for etravirine but a "susceptible" prediction for efavirenz and/or nevirapine?

Biological and clinical cut-off values represent two different approaches to evaluating quantitative FC information. With the recent addition of etravirine to the vircoTYPE HIV-1 report, both approaches are used within the NNRTI drug class. Etravirine FC information is interpreted through the application of clinical cut-offs, which were derived from an evaluation of virologic response to etravirine containing regimens in highly treatment experienced patients with confirmed evidence of pre-existing NNRTI resistance who participated in Phase IIB/III studies of this new agent. Efavirenz and nevirapine FC information is interpreted using biological cut-offs, which define the upper limit of FC values observed among genotypically wild type viruses. Since efavirenz and nevirapine are almost exclusively used in patients without evidence of resistance to the NNRTI class, it has not yet been possible to define clinical cut-offs for these two drugs. The vircoTYPE report notes the select patient population used to define the etravirine CCOs, and cautions that the performance of these cut-offs for patients different than those in the Phase IIb/III studies has not yet been evaluated. As with all drugs, Virco will continue to collect additional outcome data for patients treated with etravirine containing regimens and periodically refine the clinical cut-offs to provide the most up to date resistance interpretations possible.

In a recent review of a number of cases with ETR FC values leading to a "reduced response" interpretation while efavirenz and nevirapine were both interpreted as "susceptible", two main types of samples were identified. In some cases, calculated FC values for EFV, NVP, and ETR for the sample were similar, and fell within the relatively narrow zone between the ETR CCO1 of 1.6 and the EFV BCO of 3.3. In these cases, the two different methods of interpreting FC information are the main driver of differing resistance analyses. In other cases, the ETR FC, while still low, was higher than the FC for EFV and/or NVP, without any of the commonly recognized NNRTI resistance mutations shown on pg 1 of the vircoTYPE report. Several previously undescribed variants in reverse transcriptase considered by the virtualPhenotype-LM were associated with the higher FC for etravirine, including 138A and 189I.

It is important for the user of the vircoTYPE HIV -1 report to fully understand that a reduced response classification does not indicate that high level resistance has been detected to this drug and that it is no longer active against the virus that was analyzed. Reduced response indicates that in comparison to the full response expected for this drug against a wild type virus, there is some loss of response expected. When a reduced response interpretation is shown on page one of the vircoTYPE report, the user is encouraged to refer to page two for a more granular view of how much loss of the wild type response is expected.
 

Why is your CCO1 for ETR below the BCO?

For a number of drugs (not just etravirine), the lower clinical cut-off on the vircoTYPE report, based on virologic response in treated patients, is lower than the BCO, which is defined based on the upper limit of the range of measured FC values among clinical isolates lacking recognized resistance associated mutations. It is important for the user of the vircoTYPE HIV -1 report to fully understand that a "reduced response" classification based on the clinical cut-offs does not indicate that high level resistance has been detected to this drug and that it is no longer active against the virus that was analyzed. Rather, a reduced response classification indicates that in comparison to the full response expected for this drug against a fully susceptible wild type virus, there is some loss of response expected. When a reduced response interpretation is shown on page one of the vircoTYPE report, the user is encouraged to refer to page two for a more granular view of how much loss of the wild type response is expected. Isolates with vircoTYPE FC values between CCO1 and a higher BCO do carry mutations, recognized by the virtualPhenotype-LM, that differentiate them from a fully susceptible wild type virus and result in a higher calculated FC. For such isolates the predicted loss of response is usually moderate, and in such case substantial activity of the drug against that particular virus can be anticipated.