<!--#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 101


HIVdb Algorithm: Comments & Scores
  • K101E is a nonpolymorphic mutation that causes intermediate resistance to NVP (~5-fold reduced susceptibility) and low-level resistance (~2-fold reduced susceptibility) to EFV, ETR and RPV. It has a weight of 1.0 in the Tibotec ETR genotypic susceptibility score. In combination with M184I it reduces RPV susceptibility by about 5-fold.
  • K101H is a nonpolymorphic accessory NNRTI-resistance mutation selected by NVP, EFV and ETR. When present with other NNRTI-resistance mutations, K101H further reduces susceptibility to these NNRTIs. It has a weight of 1.0 in the Tibotec ETR genotypic susceptibility score.
  • K101N/A/T are uncommon nonpolymorphic NNRTI-selected mutation of uncertain phenotypic and clinical significance.
  • K101P is a nonpolymorphic mutation that causes high-level resistance (>50-fold reduced susceptibility) to NVP, EFV and RPV and intermediate resistance (~5-fold reduced susceptibility) to ETR. It has a weight of 2.5 in the Tibotec ETR genotypic susceptibility score.
  • K101Q is a relatively nonpolymorphic mutation that is weakly selected in patients receiving NVP and EFV. It is of uncertain phenotypic and clinical significance.
  • K101R is an uncommon polymorphism that is not associated with reduced NNRTI susceptibility.

MutationEFVNVPETRRPV
K101E15301530
K101H15151010
K101N0000
K101P60604560
K101Q0000
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 101 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
205
B
4133
C
551
D
127
F
82
G
146
AE
325
AG
78
 
A
635
B
10956
C
3765
D
418
F
275
G
874
AE
1636
AG
823
101 K T 0.5
R 0.5
Q 0.9
R 0.8
Q 1.3
R 1.3
E 0.5
Q 0.8
R 0.8
E 0.8
 Q 1.4
E 0.7
 Q 1.3  E 4.7
Q 2.3
P 0.8
H 0.5
E 5.5
Q 3.7
P 1.4
H 1.2
R 1.2
E 6.6
Q 1.5
P 0.9
H 0.9
R 0.5
E 5.7
Q 2.5
H 0.5
E 6.4
Q 3.4
P 1.5
E 6.5
Q 1.2
H 0.9
P 0.8
R 0.7
E 14
Q 2.9
P 1.9
H 1.8
R 1.7
E 5.7
Q 1.9
R 0.6
H 0.5
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
K101A006065790.00 
K101A>=1057510  
K101A>=0>=120739270.100.000
K101A>=0NVP426860.100.000
K101A>=0EFV386940.100.001
K101A>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101D00606570  
K101D>=1057510  
K101D>=0>=120739120.000.000
K101D>=0NVP426810.000.080
K101D>=0EFV386910.000.064
K101D>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101E00606571460.20 
K101E>=105751300.500.000
K101E>=0>=12073915307.300.000
K101E>=0NVP42683869.000.000
K101E>=0EFV38692626.700.000
K101E>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101H006065750.00 
K101H>=10575120.000.230
K101H>=0>=1207392161.000.000
K101H>=0NVP4268360.800.000
K101H>=0EFV3869290.700.000
K101H>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101I006065760.00 
K101I>=10575120.000.310
K101I>=0>=120739110.000.001
K101I>=0NVP426810.000.950
K101I>=0EFV386940.100.000
K101I>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101N0060657100.00 
K101N>=10575110.000.628
K101N>=0>=120739660.300.000
K101N>=0NVP426870.100.000
K101N>=0EFV3869160.400.000
K101N>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101P006065720.00 
K101P>=1057510  
K101P>=0>=1207392521.200.000
K101P>=0NVP426870.100.000
K101P>=0EFV3869571.400.000
K101P>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101Q00606573970.60 
K101Q>=105751691.100.000
K101Q>=0>=1207398394.000.000
K101Q>=0NVP42681162.700.000
K101Q>=0EFV38691263.200.000
K101Q>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101R00606576181.00 
K101R>=105751470.800.162
K101R>=0>=1207393151.500.000
K101R>=0NVP4268681.500.001
K101R>=0EFV3869451.100.435
K101R>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
K101T006065790.00 
K101T>=10575130.000.134
K101T>=0>=120739230.100.000
K101T>=0NVP426850.100.000
K101T>=0EFV386940.100.001
K101T>=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 101.
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 K101 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with K101 (not just the top 10 most frequent patterns) can be found at this page.

Mutation PatternsNumber of
Sequences
NVP
foldn
EFV
foldn
ETR
foldn
101E,190A51220098393.43
101E,181C,190A499200199920134
101E2595.2122.1121.87
101P,103N2052001520015389
101E,190S176200820071.23
101E,181C14520054.0510.03
101E,181C,190S118200220029.12
101E,103N,190A80   
101E,103N71200120011.41
101P6017155055.26
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 101.

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.