Education > Clinical Updates

Clinical Update #14 - 17th International HIV Drug Resistance Workshop

Sitges, Spain
June 10-14, 2008


Phenotypic susceptibility to the first generation NNRTIs (efavirenz and nevirapine) is significantly affected by single mutations in the HIV viral genome. Data from the DUET studies demonstrate that etravirine has a higher barrier to resistance and retains significant efficacy in patients with HIV resistant to first generation NNRTIs. Lee Bacheler and colleagues from Virco presented a poster at the 17th International HIV Drug Resistance Workshop that showed that the majority of routine clinical samples analyzed by Virco over a three year period were fully susceptible to etravirine. Among samples that demonstrated any degree of resistance,the majority had
low phenotypic fold changes indicating that etravirine retained significant antiviral activity against these isolates.


This study used the most recent version of virco®TYPE HIV-1 system (version 4.2.01) to assess susceptibility to etravirine among 93,500 routine clinical samples submitted to Virco between January 2005 to November 2007. The Virtual Phenotype™ LM bioinformatics engine considers all mutations in a sample virus and assigns weights based on their contribution to phenotypic fold change . Of particular note, the K103N mutation is not included in the calculation of etravirine fold-change. Instead, the strongest effects on etravirine fold change calculation were assigned to 101P, 179F, 181G/I/S/N/V, 190E, 230I, and 234F.


Two clinical cut-offs (1.6 and 27.6) have previously been defined for etravirine which represent 20 and 80% loss of the expected wild type response when the drug is administered in combination ARV regimens . Fold change values below the lower clinical cut-off are classified as maximal response, between the two cut-offs as reduced response and above the upper cut-off as minimal response.
As fold change increases across this continuum there is a gradual loss or response to the entire regimen due to increasing ETR resistance. Because the reduced response category spans a broad range of fold-change values, a further subdivision was explored based on an etravirine fold-change value of 5.0, which was associated with a 50% loss of activity.


Among the 93,000 routine samples analyzed, 73% demonstrated fold-change values <1.6 and were classified as "maximal response" and 90% had fold-change values <5 . Etravirine would be expected to demonstrate substantial antiviral activity against all of these isolates. In the subset of routine clinical samples that demonstrated genotypic evidence of resistance to 1st generation NNRTIs, approximately 75% had etravirine fold-change values <5.


The authors applied the fold-change categories of <1.6, 1.6 to 5.0, 5.0 to 27.6, and >27.6 to determine 24-week response rates (HIV RNA <50 copies/mL, (dropouts = failures)) to etravirine containing regimens in two patient populations, the DUET studies and a larger group that includes both the DUET studies and four Phase IIB studies. Response to etravirine containing regimens was highest in the group of patients with etravirine fold change values < 1.6 and gradually declined as fold change increased.


The authors concluded that the majority of the routine clinical samples analyzed by Virco, even those with genotypic evidence of resistance to first generation NNRTIs, demonstrated low phenotypic fold change values and that many patients would likely benefit from treatment with etravirine as part of a HAART regimen.


If you are interested in viewing the complete poster, please click here.





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