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Education > Clinical Updates

Clinical Update #8 - News from the 15^th Conference on Retroviruses and Opportunistic Infections

Boston, Massachusetts
February 3-7, 2008

Phenotypic susceptibility of the first-generation NNRTIs (efavirenz, nevirapine, delavirdine) can be significantly compromised by a single amino acid substitution resulting in loss of virologic activity. Etravirine (TMC125), a new next-generation NNRTI, demonstrates a different resistance pathway from the first-generation NNRTIs. Clinical trial data show that accumulation of >3 etravirine resistance-associated mutations is needed before significant loss of virologic activity occurs. Bart Winters and colleagues from Virco, presented data at the 15^th Conference on Retroviruses and Opportunistic Infections on the development of virco®TYPE HIV-1 clinical cut-off values for etravirine based on treatment response data from etravirine phase II/III studies. Using the same consistent approach employed for all other antiretroviral agents included on the virco®TYPE HIV-1 report, they reported two clinical cut-off values for etravirine, 1.6 and 27.6.

The group used clinical isolates with both drug susceptibility by a conventional measured phenotype (Antivirogram®) and viral genotype data and multiple linear regression modeling to calculate etravirine fold change values from the viral genotype (VirtualPhenotype™-LM). Treatment response data (DUET 1 and 2, and four phase II studies) were used to develop a separate linear regression model to predict 8-week fold change in viral load for regimens including etravirine. This model was adjusted for baseline HIV RNA, activity of the other drugs used in combination with etravirine (continuous Phenotypic Susceptibility Score, cPSS), etravirine fold-change values, and enfuvirtide use. The two clinical cut-off values (1.6 and 27.6) corresponded to calculated fold-change values associated with 20% and 80% loss of etravirine response.

There was a stronger association of baseline etravirine susceptibility with clinical response (HIV RNA reduction >1 log₁₀ copies/mL) at week 8 when clinical cut-off values were compared with biologic cut-off values (odds ratio 3.7 versus 2.1). Importantly, regimen responses observed at 24 weeks continued to be strongly associated with baseline etravirine susceptibility. Median changes from baseline in viral load at 24 weeks were: -2.66, -2.16, and 0.6 log₁₀ copies/mL, for subjects with baseline etravirine FC <1.6, between 1.6 and 27.6, or >27.6, respectively. In the CCO study population, 55%, 37%, and 26% of subjects with etravirine baseline fold change of <1.6, 1.6 to 26.6, and >27.6 achieved HIV RNA <50 copies/mL at week 24 on their etravirine containing regimen by a conservative, missing data = non responder analysis.

While previous attempts to define clinical cut-offs for first-generation NNRTIs have not been successful, these results demonstrate that a clinically relevant intermediate range of activity for etravirine has been defined. The applicability of these clinical cut-off values to patients different from those participating in etravirine phase II/III clinical studies has not yet been defined.

You can VIEW the complete poster on virco®TYPE HIV-1 Clinical Cut-Offs for INTELENCE™/TMC125/Etravirine here. If you would like to download a copy for yourself, please use the link below.
DOWNLOAD a copy of the virco®TYPE HIV-1 Clinical Cut-Offs for INTELENCE™/TMC125/Etravirine poster here.

 

These updates are effective immediately and are already available from many lab providers. For local availability or additional information, please contact your local lab provider, or Virco at: www.vircolab.com or 1-877-466-5242

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