Mutation ARV - Evidence

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MARVEL on RT mutations at position 179

HIVdb Algorithm: Comments & Scores

V179D/E cause low-level reductions in susceptibility to NVP, EFV, and DLV. V179D occurs in about 1% of untreated persons and reduces the susceptibility of each NNRTI by about 2-fold. The combination of K103R + V179D reduces the susceptibility of NVP, DLV, and EFV by about 15-fold; the combination's effect on ETR is not known. V179D was associated with a decreased response to ETR in the DUET studies.
V179D/E cause low-level reductions in susceptibility to NVP, EFV, and DLV. V179D occurs in about 1% of untreated persons and reduces the susceptibility of each NNRTI by about 2-fold. The combination of K103R + V179D reduces the susceptibility of NVP, DLV, and EFV by about 15-fold; the combination's effect on ETR is not known. V179D was associated with a decreased response to ETR in the DUET studies.
V179F nearly always occurs in combination with Y181C. By itself, V179F has no effect on ETR susceptibility but in combination with Y181C, it reduces ETR susceptibility >100-fold and causes low-level EFV resistance. It is selected in vivo by ETR.
V179I is a common polymorphism which occurs more commonly in NNRTI-treated isolates. However, it does not reduce NNRTI susceptibility.
V179T is a rare mutation that was weakly associated with a decreased response to ETR in the DUET studies. It has no apparent effect on NNRTI susceptibility

Mutation	DLV	EFV	NVP	ETR
V179D	10	10	10	10
V179E	10	10	10	10
V179F	30	15	30	15
V179I	0	0	0	0
V179T	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 179 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
179	V	I ⁵⁹ T ^0.6	I ^3.4 D ^0.6	I ^3.3 A ^0.7	I ^5.0 T ^0.8 D ^0.8	I ^5.1	E ^4.3 I ^0.7	I ¹² D ^1.0 T ^0.6	I ^5.5	I ⁷⁰ T ^1.1	I ^9.0 D ^1.9 E ^0.8	I ^3.5 D ^3.1	I ^7.4 D ^1.0	I ^4.9 D ^2.5 T ^0.6 L ^0.6 E ^0.6	E ^7.4 I ^0.7	I ¹⁸ D ^3.3 T ^1.2 E ^0.9	I ^4.9 E ^3.3 M ^0.8
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
V179A	0	0	47514	114	0.20
V179A	>=1	0	5250	10	0.10	0.581
V179A	>=0	>=1	13069	11	0.00	0.001
V179A	>=0	NVP	3877	4	0.10	0.124
V179A	>=0	EFV	2427	2	0.00	0.175
V179A	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
V179D	0	0	47514	689	1.40
V179D	>=1	0	5250	36	0.60	0.000
V179D	>=0	>=1	13069	282	2.10	0.000
V179D	>=0	NVP	3877	52	1.30	0.634
V179D	>=0	EFV	2427	103	4.20	0.000
V179D	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
V179E	0	0	47514	249	0.50
V179E	>=1	0	5250	16	0.30	0.042
V179E	>=0	>=1	13069	150	1.10	0.000
V179E	>=0	NVP	3877	30	0.70	0.055
V179E	>=0	EFV	2427	45	1.80	0.000
V179E	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
V179F	0	0	47514	2	0.00
V179F	>=1	0	5250	0
V179F	>=0	>=1	13069	37	0.20	0.000
V179F	>=0	NVP	3877	2	0.00	0.023
V179F	>=0	EFV	2427	4	0.10	0.000
V179F	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
V179G	0	0	47514	18	0.00
V179G	>=1	0	5250	4	0.00	0.350
V179G	>=0	>=1	13069	17	0.10	0.000
V179G	>=0	NVP	3877	1	0.00	0.956
V179G	>=0	EFV	2427	6	0.20	0.000
V179G	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
V179I	0	0	47514	4059	8.50
V179I	>=1	0	5250	355	6.70	0.000
V179I	>=0	>=1	13069	1700	13.00	0.000
V179I	>=0	NVP	3877	588	15.10	0.000
V179I	>=0	EFV	2427	158	6.50	0.001
V179I	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
V179L	0	0	47514	6	0.00
V179L	>=1	0	5250	1	0.00	0.803
V179L	>=0	>=1	13069	20	0.10	0.000
V179L	>=0	NVP	3877	3	0.00	0.022
V179L	>=0	EFV	2427	4	0.10	0.000
V179L	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
V179M	0	0	47514	3	0.00
V179M	>=1	0	5250	1	0.00	0.865
V179M	>=0	>=1	13069	16	0.10	0.000
V179M	>=0	NVP	3877	6	0.10	0.000
V179M	>=0	EFV	2427	4	0.10	0.000
V179M	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
V179T	0	0	47514	115	0.20
V179T	>=1	0	5250	9	0.10	0.394
V179T	>=0	>=1	13069	38	0.20	0.377
V179T	>=0	NVP	3877	14	0.30	0.208
V179T	>=0	EFV	2427	3	0.10	0.338
V179T	>=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 179.

Mutation pattern data is not available for V179.

A complete summary of additional in vitro susceptibility data for viruses with V179 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 179.

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 179

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