Mutation ARV - Evidence

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MARVEL on RT mutations at position 103

HIVdb Algorithm: Comments & Scores

K103E/Q are rare mutations that have not been associated with resistance to the current NNRTIs.
K103T/H are rare mutations that appear to be associated with intermediate/high-level resistance to NVP, DLV, and EFV.
K103N causes high-level resistance to NVP, DLV, and EFV. By itself it has no effect on ETR susceptibility. However, it has a synergistic effect with L100I and possibly K101P on ETR susceptibility.
K103E/Q are rare mutations that have not been associated with resistance to the current NNRTIs.
K103R occurs in about 1%-2% of untreated persons and by itself has no effect on NNRTI susceptibility. However, the combination of K103R + V179D, reduces NVP, DLV, and EFV susceptibility by about 15-fold.
K103S causes high-level resistance to NVP and intermediate/high-level resistance to DLV and EFV.
K103T/H are rare mutations that appear to be associated with intermediate/high-level resistance to NVP, DLV, and EFV.

Mutation	DLV	EFV	NVP	ETR
K103E	0	0	0	0
K103H	0	0	0	0
K103N	60	60	60	5
K103Q	0	0	0	0
K103R	5	5	5	0
K103S	60	60	60	5
K103T	60	60	60	5

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 103 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
103	K	N ^1.2	R ^2.0 N ^0.5		N ^1.6 R ^0.8	N ^2.4 R ^1.2	Q ^0.7 N ^0.7		R ^1.3	N ¹⁷ S ^0.7 Q ^0.5 E ^0.5	N ³⁸ R ^1.9 S ^1.5	N ³² R ^2.4 S ^1.5	N ¹⁸ R ^0.7	N ³⁹ S ^1.2 R ^1.2	N ⁴³ R ^1.0 S ^0.7	N ²⁶ R ^1.2 S ^0.8	N ³⁸ S ^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
K103E	0	0	48689	23	0.00
K103E	>=1	0	5257	0
K103E	>=0	>=1	13067	8	0.00	0.679
K103E	>=0	NVP	3870	3	0.00	0.660
K103E	>=0	EFV	2432	2	0.00	0.771
K103E	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K103H	0	0	48689	0
K103H	>=1	0	5257	0
K103H	>=0	>=1	13067	20	0.10	0.000
K103H	>=0	NVP	3870	1	0.00	0.103
K103H	>=0	EFV	2432	0
K103H	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K103N	0	0	48689	635	1.30
K103N	>=1	0	5257	50	0.90	0.035
K103N	>=0	>=1	13067	4947	37.80	0.000
K103N	>=0	NVP	3870	1128	29.10	0.000
K103N	>=0	EFV	2432	1263	51.90	0.000
K103N	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K103Q	0	0	48689	35	0.00
K103Q	>=1	0	5257	5	0.00	0.748
K103Q	>=0	>=1	13067	8	0.00	0.823
K103Q	>=0	NVP	3870	4	0.10	0.699
K103Q	>=0	EFV	2432	1	0.00	0.867
K103Q	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K103R	0	0	48689	1031	2.10
K103R	>=1	0	5257	107	2.00	0.731
K103R	>=0	>=1	13067	276	2.10	1.000
K103R	>=0	NVP	3870	44	1.10	0.000
K103R	>=0	EFV	2432	79	3.20	0.000
K103R	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K103S	0	0	48689	17	0.00
K103S	>=1	0	5257	3	0.00	0.677
K103S	>=0	>=1	13067	161	1.20	0.000
K103S	>=0	NVP	3870	35	0.90	0.000
K103S	>=0	EFV	2432	19	0.70	0.000
K103S	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K103T	0	0	48689	11	0.00
K103T	>=1	0	5257	4	0.00	0.076
K103T	>=0	>=1	13067	14	0.10	0.000
K103T	>=0	NVP	3870	8	0.20	0.000
K103T	>=0	EFV	2432	0
K103T	>=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 103.

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 K103 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with K103 (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
103N	5799	51₁₉₄	21₁₉₃	0.8₄₈
103N,181C	1371	200₄₈	32₅₀	6.8₁₀
100I,103N	924	71₅₂	200₄₉	6.3₁₆
103N,181C,190A	441	200₅	200₅
103N,190A	440	200₂	200₂
103S,190A	160	200₆	47₆	0.2₂
103N,230L	159	200₉	200₉	8.7₃
101P,103N	154	200₁₀	200₁₀	38₇
103N,188L	128	200₇	200₇	4.3₄
103N,106M	96	200₁	200₁
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.

MARVEL on RT mutations at position 103

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