<!--#if expr="$title" --> <!--#echo var="title" --> <!--#else --> HIV Drug Resistance Database <!--#endif -->
Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

MARVEL on RT mutations at position 181


HIVdb Algorithm: Comments & Scores
  • 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.

MutationEFVNVPETRRPV 90I0000 98G10301015 100I45453060 100V30301015 101E15301530 101P60604560 101Q0000 101H15151010 101N0000 103N606000 103R0000 103S456000 103T156000 103Q0000 103E0000 103H606000 106A456000 106M606000 106I0000 108I101500 138A001015 138K10101030 138Q10101015 138G10101015 138R10101015 179D10101010 179E10101010 179T10101010 179L10101015 179I0000 179F10151515 181C30603030 181I30606060 181V30606060 181S15601515 181F15603030 181G15603030 188C606000 188H306000 188L60601560 188F6030030 190A45601515 190S60601515 190E60604545 190Q60604545 190C60601010 190V60601010 190T60601010 221Y10101010 225H303000 227C30303030 227L153000 230L45603045 230I15301530 234I0000 236L0000 238T306000 238N101000 318F103000 348I101500
Footnote:Mutation scores on the left are derived from published literature linking mutations and ARVs (the complete details can be found in the HIVdb Release Notes).
Genotype-treatment correlation
Mutation frequency according to subtype and drug-class experience.
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.

PosWTNRTI (but no NNRTI) Treated Persons NNRTI Treated Persons
A
179
B
4133
C
461
D
127
F
82
G
146
AE
339
AG
78
 
A
543
B
8569
C
3392
D
421
F
221
G
555
AE
1617
AG
699
181 Y C 0.6  C 1.3 N 0.8
C 0.8
C 1.2
V 1.2
T 0.7 C 1.2 C 1.3  C 12
I 1.0
V 0.8
C 18
I 1.0
C 11
I 0.5
C 14
V 1.0
C 22
I 0.5
C 27
I 0.6
C 37
V 2.2
I 2.0
C 23
V 0.9
I 0.6
Footnote: The query page Mutation Prevalence According to Subtype and Treatment to examine the frequency of all mutations according to subtype and treatment; The program HIVSeq provides similar output for mutations in user-submitted sequences; A complete description of the program that generates these tables can be found at Rhee et al AIDS 2006.
 

Mutation frequency according to treatment with individual ARVs.
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.
MutationNRTINNRTINumSeqNumMut% Mutantp
Y181C00573981980.30 
Y181C>=105637460.800.000
Y181C>=0>=117441365120.900.000
Y181C>=0NVP4244142633.600.000
Y181C>=0EFV34341554.500.000
Y181C>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
Y181F0057398100.00 
Y181F>=10563720.000.665
Y181F>=0>=11744170.000.145
Y181F>=0NVP424410.000.759
Y181F>=0EFV343410.000.874
Y181F>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
Y181H005739880.00 
Y181H>=1056370  
Y181H>=0>=11744120.000.899
Y181H>=0NVP42440  
Y181H>=0EFV34340  
Y181H>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
Y181I005739880.00 
Y181I>=1056370  
Y181I>=0>=1174411570.900.000
Y181I>=0NVP4244461.000.000
Y181I>=0EFV343430.000.014
Y181I>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
Y181V005739830.00 
Y181V>=10563710.000.803
Y181V>=0>=1174411120.600.000
Y181V>=0NVP4244491.100.000
Y181V>=0EFV34340  
Y181V>=0ETR00  
Footnote: About one-half of the untreated isolates belong to non-subtype B isolates; About 20% of the treated isolates belong to non-subtype B isolates; A page containing summaries for all of the mutations at this position can be found here.

Genotype-phenotype correlation
Phenotypes of top 10 common patterns of drug resistance mutations with mutations at position 181.
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.

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 PatternsNumber of
Sequences
NVP
foldn
EFV
foldn
ETR
foldn
181C2020200691.6715.520
103N,181C14822004832506.810
181C,190A7732002083214710
101E,181C,190A4692001610117151
103N,181C,190A46420052005 
101E,181C132200410.041052
181I13120061.46 
101E,181C,190S108   
181V10020041.64531
181C,190S99200520056.51
Footnote: Mutation patterns were defined by the presence or absence of major NNRTI drug resistance mutations ; Sequences containing a mixture at a major drug resistance positions were excluded; For the cutoffs defined by PhenoSense, open the sample report form provided on this page; The full list of all mutation patterns are also available here.

 

Phenotypic coefficients using machine learning
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.

 

Genotype-clinical outcome correlation
Studies correlating baseline genotype and virological response to an ARV therapy with or without mutations at 181.

ReferencePrevious NNRTIFollow-up NNRTIOther RxNo.PtsWeeksEffect of baseline mutations on response
Madruga(2007)
Katlama (2007), Lazzarin (2007), DUET
93% had received >= 1 NNRTI. All had >=1 NNRTI resistance mutation at screening or from a historical genotypeETR vs placeboDRV/RTV + OB4062413 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.
Vingerhoets(2008)
DUET follow-up study
93% had received >= 1 NNRTI. All had >=1 NNRTI resistance mutation at screening or from a historical genotypeETR vs placeboDRV/RTV + OB406243 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.
Abbreviations:
    OB - optimized background; VR - virologic response;

References:
  • Madruga J.V., Cahn P., Grinsztejn B., Haubrich R., Lalezari J., Mills A., Pialoux G., Wilkin T., Peeters M., Vingerhoets J., de Smedt G., Leopold L., Trefiglio R., Woodfall B. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):29-38.
  • Vingerhoets J., Peeters M., Azijn H., Tambuyzer L., Hoogstoel A., Nijs S., de Bethune M-P., Picchio G. An update of the list of NNRTI mutations associated with decreased virological response to etravirine: multivariate analyses on the pooled DUET-1 and DUET-2 clinical trial data [abstract 24]. Antiviral Therapy. 2008; 13 Suppl 3:A26.