Mutation ARV - Evidence

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MARVEL on RT mutations at position 181

HIVdb Algorithm: Comments & Scores

Y181C/I/V cause high-level resistance to NVP and DLV and low-level resistance to EFV. Y181C/I/V reduces ETR susceptibility by 5 to 15-fold and provide the mutational foundation for the development of higher levels of ETR resistance. Y181C increases susceptibility to AZT and TDF.
Y181C/I/V cause high-level resistance to NVP and DLV and low-level resistance to EFV. Y181C/I/V reduces ETR susceptibility by 5 to 15-fold and provide the mutational foundation for the development of higher levels of ETR resistance. Y181C increases susceptibility to AZT and TDF.
Y181C/I/V cause high-level resistance to NVP and DLV and low-level resistance to EFV. Y181C/I/V reduces ETR susceptibility by 5 to 15-fold and provide the mutational foundation for the development of higher levels of ETR resistance. Y181S is a rare NNRTI-selected mutation that causes intermediate-high resistance to NVP and DLV. Few data are available for EFV and ETR.
Y181C/I/V cause high-level resistance to NVP and DLV and low-level resistance to EFV. Y181C/I/V reduces ETR susceptibility by 5 to 15-fold and provide the mutational foundation for the development of higher levels of ETR resistance. Y181C increases susceptibility to AZT and TDF.

Mutation	DLV	EFV	NVP	ETR
Y181C	60	30	60	35
Y181I	60	30	60	45
Y181S	60	30	60	20
Y181V	60	30	60	45

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.

Pos	WT	NRTI (but no NNRTI) Treated Persons								NNRTI Treated Persons
Pos	WT	A 172	B 3960	C 288	D 126	F 83	G 142	AE 325	AG 75	A 463	B 8280	C 1994	D 304	F 169	G 428	AE 790	AG 403
181	Y	C ^0.6		C ^0.7	N ^0.8 C ^0.8	C ^1.2 V ^1.2	T ^0.7	C ^1.2	C ^1.3	C ¹³ I ^0.9 V ^0.7	C ²⁰ I ^1.0 V ^0.5	C ¹² I ^0.7 V ^0.6	C ¹² V ^0.7	C ²⁵ I ^0.6	C ³¹ I ^0.5 V ^0.5	C ³⁴ I ^1.5 V ^1.3	C ³² V ^1.3 I ^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.

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
Y181C	0	0	48698	159	0.30
Y181C	>=1	0	5253	39	0.70	0.000
Y181C	>=0	>=1	13076	2954	22.50	0.000
Y181C	>=0	NVP	3875	1304	33.60	0.000
Y181C	>=0	EFV	2433	98	4.00	0.000
Y181C	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
Y181F	0	0	48698	9	0.00
Y181F	>=1	0	5253	1	0.00	0.614
Y181F	>=0	>=1	13076	7	0.00	0.057
Y181F	>=0	NVP	3875	1	0.00	0.775
Y181F	>=0	EFV	2433	1	0.00	0.975
Y181F	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
Y181I	0	0	48698	6	0.00
Y181I	>=1	0	5253	0
Y181I	>=0	>=1	13076	119	0.90	0.000
Y181I	>=0	NVP	3875	42	1.00	0.000
Y181I	>=0	EFV	2433	3	0.10	0.001
Y181I	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
Y181V	0	0	48698	3	0.00
Y181V	>=1	0	5253	1	0.00	0.852
Y181V	>=0	>=1	13076	75	0.50	0.000
Y181V	>=0	NVP	3875	43	1.10	0.000
Y181V	>=0	EFV	2433	0
Y181V	>=0	ETR	0	0

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 Patterns	Number of Sequences	NVP fold_n	EFV fold_n	ETR fold_n
181C	1667	200₆₉	1.6₇₁	5.5₂₀
103N,181C	1371	200₄₈	32₅₀	6.8₁₀
181C,190A	689	200₂₀	83₂₁	47₁₀
103N,181C,190A	441	200₅	200₅
101E,181C,190A	409	200₁₆	101₁₇	15₁
101E,181C	112	200₄	10.0₄	105₂
181I	107	200₆	1.4₆
101E,181C,190S	96
181C,190S	93	200₅	200₅	6.5₁
181V	76	200₄	1.6₄	53₁
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.

Reference

Previous NNRTI

Follow-up NNRTI

Other Rx

No.Pts

Weeks

Effect 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 genotype

ETR vs placebo

DRV/RTV + OB

406

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.

Vingerhoets(2008)
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

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.

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.

MARVEL on RT mutations at position 181

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