<!--#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 100


HIVdb Algorithm: Comments & Scores
  • L100I is a nonpolymorphic mutation that usually occurs in combination with K103N. In this setting it causes high-level resistance to NVP and EFV (>50-fold reduced susceptibility), high-level resistance to RPV (>10-fold reduced susceptibility) and intermediate-level resistance to ETR (~5-fold reduced susceptibility). It has a weight of 2.5 in the Tibotec ETR genotypic susceptibility score.
  • L100V is an extremely rare nonpolymorphic mutation associated with 5 to 10-fold reduced susceptibility to NVP and EFV. It may also reduce susceptibility to ETR and RPV.

MutationEFVNVPETRRPV
L100I45453060
L100V30301015
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 100 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
100 L          I 0.9 I 5.1 I 1.8 I 1.4 I 2.9 I 4.6 I 1.0 I 1.2
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
L100F0060625270.00 
L100F>=10575140.000.603
L100F>=0>=120838130.000.411
L100F>=0NVP429820.000.754
L100F>=0EFV388110.000.882
L100F>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
L100I006062550.00 
L100I>=10575130.000.023
L100I>=0>=1208388824.200.000
L100I>=0NVP429860.100.000
L100I>=0EFV38812476.300.000
L100I>=0ETR00  
MutationNRTINNRTINumSeqNumMut% Mutantp
L100V0060625220.00 
L100V>=10575110.000.715
L100V>=0>=120838170.000.017
L100V>=0NVP429820.000.944
L100V>=0EFV388150.100.020
L100V>=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 100.
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 L100 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with L100 (not just the top 10 most frequent patterns) can be found at this page.

Mutation PatternsNumber of
Sequences
NVP
foldn
EFV
foldn
ETR
foldn
100I,103N11497162200596.825
100I,188L34200220021172
100I,103N,181C2720012001 
100I262.649.741.97
100I,103N,190A16   
100I,103N,181I14   
100I,103N,181C,190A11   
100I,103N,230L8   
100I,103N,106M8   
100I,103S7211150016.51
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 100.

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.