<!--#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 138


HIVdb Algorithm: Comments & Scores
  • E138A is a common polymorphic accessory mutation weakly selected in patients receiving ETR and RPV. It reduces ETR and RPV susceptibility ~2-fold. It has a weight of 1.5 in the Tibotec ETR genotypic susceptibility score.
  • E138K is a nonpolymorphic mutation selected in a high proportion of patients receiving RPV. Alone it causes low-level RPV resistance (2 to 3-fold reduced susceptibility). However, in combination with the NRTI-resistance mutation M184I it appears sufficient to cause virological failure on an RPV-containing regimen. E138K causes low-level cross-resistance to ETR but minimal, if any, cross-resistance to NVP and EFV.
  • E138Q/G are nonpolymorphic accessory mutations frequently selected in patients receiving ETR and RPV and occasionally in patients receiving NVP and EFV. E138Q/G are associated with 2 to 3-fold reduced susceptibility to ETR and RPV.
  • E138R is a rare nonpolymorphic accessory mutation selected in vitro by RPV. It is associated with 2 to 3-fold reduced susceptibility to ETR and RPV.

MutationEFVNVPETRRPV
E138A001015
E138G10101015
E138K10101030
E138Q10101015
E138R10101015
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 138 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
138 E A 4.7
K 1.0
G 0.5
A 1.8 A 7.6
K 1.0
G 0.8 A 1.3 A 3.5
K 1.4
K 0.6 A 1.3  A 2.2
Q 0.8
A 2.2
Q 0.5
A 6.4
K 0.6
Q 0.6
A 2.2 A 2.6
G 1.1
Q 0.7
A 2.9
Q 1.9
K 0.5
Q 2.5
A 1.1
G 0.9
A 2.6
Q 1.5
G 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
E138A004839512752.60 
E138A>=1057491452.500.645
E138A>=0>=1208296513.100.000
E138AAZT>=0453102.200.676
E138ADDI>=05323.700.929
E138AD4T>=0550  
E138AABC>=04712.100.811
E138A>=0NVP42961252.900.305
E138A>=0EFV38831564.000.000
E138A>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
E138D0048395160.00 
E138D>=10574960.100.029
E138D>=0>=120829150.000.043
E138DAZT>=04530  
E138DDDI>=0530  
E138DD4T>=0550  
E138DABC>=0470  
E138D>=0NVP429620.000.975
E138D>=0EFV388330.000.341
E138D>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
E138G00483951160.20 
E138G>=105749100.100.404
E138G>=0>=1208291380.600.000
E138GAZT>=04530  
E138GDDI>=0530  
E138GD4T>=0550  
E138GABC>=0470  
E138G>=0NVP4296220.500.001
E138G>=0EFV3883190.400.005
E138G>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
E138K0048395620.10 
E138K>=105749210.300.000
E138K>=0>=120829760.300.000
E138KAZT>=04530  
E138KDDI>=0530  
E138KD4T>=0550  
E138KABC>=0470  
E138K>=0NVP429680.100.433
E138K>=0EFV3883240.600.000
E138K>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
E138Q0048395150.00 
E138Q>=10574980.100.001
E138Q>=0>=1208292311.100.000
E138QAZT>=04530  
E138QDDI>=0530  
E138QD4T>=0550  
E138QABC>=0470  
E138Q>=0NVP4296671.500.000
E138Q>=0EFV3883260.600.000
E138Q>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
E138R004839530.00 
E138R>=1057490  
E138R>=0>=12082940.000.251
E138RAZT>=04530  
E138RDDI>=0530  
E138RD4T>=0550  
E138RABC>=0470  
E138R>=0NVP42960  
E138R>=0EFV388350.100.000
E138R>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
E138S0048395160.00 
E138S>=10574920.000.753
E138S>=0>=120829110.000.319
E138SAZT>=04530  
E138SDDI>=0530  
E138SD4T>=0550  
E138SABC>=0470  
E138S>=0NVP429620.000.975
E138S>=0EFV388350.100.014
E138S>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
E138T004839510.00 
E138T>=1057490  
E138T>=0>=120829110.000.000
E138TAZT>=04530  
E138TDDI>=0530  
E138TD4T>=0550  
E138TABC>=0470  
E138T>=0NVP429610.000.384
E138T>=0EFV388310.000.343
E138T>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
E138V004839550.00 
E138V>=10574950.000.000
E138V>=0>=12082930.000.944
E138VAZT>=04530  
E138VDDI>=0530  
E138VD4T>=0550  
E138VABC>=0470  
E138V>=0NVP42960  
E138V>=0EFV38830  
E138V>=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 138.
Mutation pattern data is not available for E138.

A complete summary of additional in vitro susceptibility data for viruses with E138 obtained using other assays including the Antivirogram can be found 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 138.

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.