Clinical cut-offs for HIV-1 phenotypic resistance estimates: Update based on recent pivotal clinical trial data and a revised approach to viral mixtures

Resistance-Associated Mutations to Etravirine (TMC-125) in Antiretroviral-Naïve Patients Infected with Non-B HIV-1 Subtypes

“…This finding is in accordance with the facts Previous studies suggested that E138A may have a significant impact on ETR resistance, and its presence has been associated with decreased virological response to ETR in multivariate analyses (3,12,18). Additionally, the virtual phenotype linear model predicted intermediate changes of 2-to 10-fold in the ETR IC 50 for E138A virus (26). Thus, it may be possible that the presence of the E138A mutation alone was responsible for the observed increase in resistance to ETR, but the E138A sample also contained the V179I mutation in the RT gene.…”

Novel Method for Simultaneous Quantification of Phenotypic Resistance to Maturation, Protease, Reverse Transcriptase, and Integrase HIV Inhibitors Based on 3′Gag(p2/p7/p1/p6)/PR/RT/INT-Recombinant Viruses: a Useful Tool in the Multitarget Era of Antiretroviral Therapy

“…Although the BCOs calculated for our new HIV-1 phenotyping assay are comparable to those determined for the two most utilized HIV-1 phenotyping assays (28,50,51,73), these BCOs are still a work in progress and will be periodically updated as additional wildtype viruses are continually analyzed and added to our database. On the other hand, clinical cutoffs (CCOs) may have greater relevance since in vitro data (i.e., fold changes) are compared to clinical response information from treatmentexperienced patients before and after a defined period of antiretroviral therapy (81,82). Therefore, future studies will be designed to determine CCOs for each antiretroviral drug using this novel HIV-1 phenotyping assay.…”

Residual Activity of Two HIV Antiretroviral Regimens Prescribed without Virological Monitoring

“…A key objective in clinical research has been the identification of cut-points for phenotypic resistance assays that signify when the effect of a drug ceases to exert meaningful clinical activity (3,29,30). However, threshold effects often lack biological plausibility, and arbitrary statistical rules underlie selection of cut-points.…”

“…3B in their paper) casts doubt on the reliability of these values; for example, there were only 10 samples with abacavir FC values above 7. Winters and colleagues sought to identify cut-points by fitting linear regression models to a large, combined clinical trial and cohort data set, on the basis of loss of drug activity relative to that for wild-type virus, using HIV RNA response at 8 weeks (29,30). They estimated 80% loss of abacavir activity at an FC value of 3.5, although this was a predicted, rather than a directly measured, FC value based on a genotypic algorithm.…”

“…Samples with HIV RNA above the linear dynamic range which met the inclusion criteria for the current analysis (see below) were retested after 2-to 10-fold dilution to achieve uncensored values. Genotypic (VircoTYPE 4.3.01) (29,30) and phenotypic (Antivirogram 2.5.01, Virco BVBA) (16) resistance testing was performed on samples with HIV-1 RNA of Ն1,000 copies/ml at 48/96 weeks and on the corresponding baseline samples. For each drug, phenotypic resistance was expressed as the fold change (FC) in 50% inhibitory concentration (IC 50 ) compared to that of wild-type (HXB2) virus.…”