Mutation ARV - Evidence

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MARVEL on RT mutations at position 101

HIVdb Algorithm: Comments & Scores

K101E causes intermediate resistance to NVP and DLV and low-level resistance to EFV and ETR.
K101H/N are rare NNRTI-associated mutations with uncertain phenotypic and clinical effects. K101H was weakly associated with a decreased ETR response in the DUET studies.
K101H/N are rare NNRTI-associated mutations with uncertain phenotypic and clinical effects. K101H was weakly associated with a decreased ETR response in the DUET studies.
K101P nearly always occurs with K103N and in this setting causes high-level resistance to NVP, DLV, and EFV. By itself K101P reduces ETR susceptibility 6-fold.
K101Q is weakly associated with NNRTI therapy and minimally reduces susceptibility to each of the NNRTIs.
K101R is an uncommon polymorphism that has not been associated with decreased NNRTI susceptibility.

Mutation	DLV	EFV	NVP	ETR
K101E	30	15	30	10
K101H	15	10	15	5
K101N	15	10	15	5
K101P	40	40	40	20
K101Q	5	5	5	5
K101R	0	0	0	0

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.

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
101	K	T ^0.6	Q ^0.8 R ^0.8	R ^1.7 Q ^1.4 E ^0.7	Q ^0.8 R ^0.8 E ^0.8		Q ^1.4 E ^0.7		Q ^1.3	E ^4.0 Q ^2.2 P ^1.1 H ^0.7	E ^6.3 Q ^4.4 P ^1.8 H ^1.4 R ^1.0	E ^5.7 Q ^1.3 H ^0.8	E ^3.1 Q ^1.7	E ^6.8 Q ^4.9 P ^2.5 H ^0.6	E ^7.7 Q ^1.7 H ^1.2 R ^1.0 P ^0.7	E ¹² Q ^3.1 R ^2.4 P ^1.8 H ^1.0	E ^7.5 Q ^1.5 R ^0.8 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.

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101A	0	0	48701	9	0.00
K101A	>=1	0	5257	0
K101A	>=0	>=1	13028	15	0.10	0.000
K101A	>=0	NVP	3852	4	0.10	0.007
K101A	>=0	EFV	2425	3	0.10	0.009
K101A	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101E	0	0	48701	124	0.20
K101E	>=1	0	5257	24	0.40	0.012
K101E	>=0	>=1	13028	987	7.50	0.000
K101E	>=0	NVP	3852	329	8.50	0.000
K101E	>=0	EFV	2425	140	5.70	0.000
K101E	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101H	0	0	48701	4	0.00
K101H	>=1	0	5257	2	0.00	0.208
K101H	>=0	>=1	13028	150	1.10	0.000
K101H	>=0	NVP	3852	28	0.70	0.000
K101H	>=0	EFV	2425	18	0.70	0.000
K101H	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101I	0	0	48701	6	0.00
K101I	>=1	0	5257	2	0.00	0.390
K101I	>=0	>=1	13028	7	0.00	0.011
K101I	>=0	NVP	3852	1	0.00	1.000
K101I	>=0	EFV	2425	2	0.00	0.062
K101I	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101N	0	0	48701	9	0.00
K101N	>=1	0	5257	1	0.00	0.613
K101N	>=0	>=1	13028	40	0.30	0.000
K101N	>=0	NVP	3852	6	0.10	0.000
K101N	>=0	EFV	2425	10	0.40	0.000
K101N	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101P	0	0	48701	1	0.00
K101P	>=1	0	5257	0
K101P	>=0	>=1	13028	174	1.30	0.000
K101P	>=0	NVP	3852	6	0.10	0.000
K101P	>=0	EFV	2425	37	1.50	0.000
K101P	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101Q	0	0	48701	313	0.60
K101Q	>=1	0	5257	60	1.10	0.000
K101Q	>=0	>=1	13028	614	4.70	0.000
K101Q	>=0	NVP	3852	104	2.60	0.000
K101Q	>=0	EFV	2425	87	3.50	0.000
K101Q	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101R	0	0	48701	497	1.00
K101R	>=1	0	5257	41	0.70	0.111
K101R	>=0	>=1	13028	192	1.40	0.000
K101R	>=0	NVP	3852	63	1.60	0.000
K101R	>=0	EFV	2425	30	1.20	0.353
K101R	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K101T	0	0	48701	7	0.00
K101T	>=1	0	5257	3	0.00	0.104
K101T	>=0	>=1	13028	15	0.10	0.000
K101T	>=0	NVP	3852	5	0.10	0.000
K101T	>=0	EFV	2425	1	0.00	0.841
K101T	>=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 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 Patterns	Number of Sequences	NVP fold_n	EFV fold_n	ETR fold_n
101E,181C,190A	409	200₁₆	101₁₇	15₁
101E,190A	363	200₆	120₆
101E	207	8.6₄	3.2₄	1.8₁
101P,103N	154	200₁₀	200₁₀	38₇
101E,190S	132	200₇	200₆	3.6₂
101E,181C	112	200₄	10.0₄	105₂
101E,181C,190S	96
101E,103N,190A	57
101E,103N	57
101P	56	171₅	50₅	5.2₆
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.

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 101

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