The frequency of each mutation at position 181 according to subtype and drug-class experience. Data are shown for the 8 most common subtypes. The number of persons in each subtype/treatment category is shown beneath the subtype. Mutations occurring at a frequency >0.5% are shown. Each mutation is also a hyper-link to a separate web page with information on each isolate, including literature references with PubMed abstracts, the GenBank accession number, and complete sequence and treatment records.
- Y181C is a nonpolymorphic mutation selected in patients receiving NVP, ETR and RPV. It reduces susceptibility to NVP, ETR, RPV, and EFV by >50-fold, 5-fold, 3-fold, and 2-fold, respectively. Although Y181C itself reduces EFV susceptibility by only 2-fold, it is associated with a reduced response to an EFV-containing regimen because viruses with this mutation often harbor additional minority variant NNRTI-resistance mutations. Y181C has a weight of 2.5 in the Tibotec ETR GSS.
- Y181F/S/G are rare nonpolymorphic NNRTI-associated mutations that are usually present as part of an electrophoretic mixture. They are likely to represent transitional mutations between Y and I or V.
- Y181I/V are 2-base pair nonpolymorphic mutations selected by NVP and ETR. Y181I/V cause high-level resistance to NVP (>50-fold reduced susceptibility) and to ETR and RVP (10 to 15-fold reduced susceptibility). Y181I/V each have a weight of 3.0 in the Tibotec ETR genotypic susceptibility score.
The first row shows the frequency of the mutation in persons who are RTI-naive (indicated in green). The second row shows the frequency of the mutation in persons who have received one or more NRTIs (No NNRTIs). The third row shows the frequency of the mutation in persons who have received one or more NNRTIs (+/- NRTIs). The following rows show the frequency of the mutation in persons who have received only a single NNRTI. Mutation rates that differ significantly between treated and untreated isolates are indicated in yellow.
|Pos||WT||NRTI (but no NNRTI) Treated Persons|| ||NNRTI Treated Persons|
|| || ||C 2.0 ||N 0.8|
|T 0.7 ||C 1.2 ||C 1.2 || ||C 11|
|C 10 ||C 14|
|C 22 ||C 21 ||C 36|
Mutation patterns are listed in the frequency with which they have been reported in the published literature. The median level of fold resistance (compared with wildtype) for viruses with the mutation pattern in the first column are indicated when available. The subscripts indicate the number of viruses that were phenotyped. The drug susceptibility assay used was the PhenoSense assay (Monogram, South San Francisco). A hyperlink for each individual pattern is provided to access a complete list of mutations and fold resistances for each sequence matching the pattern of mutation.
|Y181C||>=0||ETR||0||0|| || |
|Y181F||>=0||ETR||0||0|| || |
|Y181H||>=0||ETR||0||0|| || |
|Y181I||>=0||ETR||0||0|| || |
|Y181V||>=0||ETR||0||0|| || |
A complete summary of additional in vitro susceptibility data for viruses with Y181 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with Y181 (not just the top 10 most frequent patterns) can be found at this page.
|Mutation Patterns||Number of|
||Least Square Regression (LSR) was used to learn the relative contribution of each mutation to the fold decrease in susceptibility for an ARV. The figure on the left (click to enlarge the figure) shows the regression coefficients (which correlate with the contribution to resistance) for the 24 nonpolymorphic NNRTI-resistance mutations shown to contribute decreased susceptibility to at least one NNRTI. A complete description of the method that generates this figure can be found at Rhee et al PNAS 2006.|
|Reference||Previous NNRTI||Follow-up NNRTI||Other Rx||No.Pts||Weeks||Effect of baseline mutations on response|
Katlama (2007), Lazzarin (2007), DUET
|93% had received >= 1 NNRTI. All had >=1 NNRTI resistance mutation at screening or from a historical genotype||ETR vs placebo||DRV/RTV + OB||406||24||13 baseline mutations were associated with a decreased response to ETR: V90I, A98G, L100I, K101EP, V106I, V179DF, Y181CIV, G190AS. When 3 or more of these mutations were present, the response to ETR was no different from placebo.|
DUET follow-up study
|93% had received >= 1 NNRTI. All had >=1 NNRTI resistance mutation at screening or from a historical genotype||ETR vs placebo||DRV/RTV + OB||406||24||3 baseline mutations were identified as associated with a decreased VR (defined by RNA <50 copies/ml) at W24: K101H, E138A and V179T in addition to the 13 (V90I, A98G, L100I, K101EP, V106I, V179DF, Y181CIV, G190AS) in Madruga 2007 study. 77% of patients with none of these 16, 61% patients with one of these 16, 56% with two and 38% with >=3 were associated with a decreased VR.|