Mutation ARV - Evidence

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MARVEL on RT mutations at position 66

HIVdb Algorithm: Comments & Scores

Amino acid deletions (d) between codons 66 to 71 are rare and usually occur in combination with multiple TAMs, the Q151M mutation complex, or K65R. Deletions at position 67 are more often associated with multiple TAMs. Deletions at position 69 are more often associated with either the Q151M complex or K65R.
Double amino acid insertions between codons 66 to 71 most often align to codon 69 and occur in less than 1% of heavily treated persons. Together with TAMs, they confer high-level resistance to AZT, d4T, ddI, ABC and TDF and intermediate/high-level resistance to 3TC and FTC.

Mutation	3TC	FTC	ABC	AZT	D4T	DDI	TDF
K66del	15	15	30	30	30	30	30
K66ins	30	30	45	45	45	45	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 66 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	RTI Naive Persons								NRTI (but no NNRTI) Treated Persons
Pos	WT	A 4366	B 32240	C 10207	D 1693	F 995	G 1800	AE 8574	AG 3223	A 279	B 4137	C 584	D 129	F 82	G 146	AE 335	AG 86
66	K	R ^0.1		R ^0.1 E ^0.1			N ^0.1	R ^0.1	T ^0.1 N ^0.1	R ^0.4		del ^0.2					N ^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 (+/- NNRTIs). The following rows show the frequency of the mutation in persons who have received only a single NRTI. Mutation rates that differ significantly between treated and untreated isolates are indicated in yellow.

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K66E	0	0	60508	10	0.00
K66E	>=1	0	5885	0
K66E	>=0	>=1	22259	7	0.00	0.292
K66E	AZT	>=0	452	0
K66E	DDI	>=0	53	0
K66E	D4T	>=0	55	0
K66E	ABC	>=0	47	0
K66E	>=0	NVP	4876	0
K66E	>=0	EFV	4514	3	0.00	0.081
K66E	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K66N	0	0	60508	12	0.00
K66N	>=1	0	5885	1	0.00	0.735
K66N	>=0	>=1	22259	9	0.00	0.160
K66N	AZT	>=0	452	0
K66N	DDI	>=0	53	0
K66N	D4T	>=0	55	0
K66N	ABC	>=0	47	0
K66N	>=0	NVP	4876	1	0.00	0.620
K66N	>=0	EFV	4514	0
K66N	>=0	ETR	0	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
K66R	0	0	60508	52	0.00
K66R	>=1	0	5885	7	0.10	0.560
K66R	>=0	>=1	22259	47	0.20	0.000
K66R	AZT	>=0	452	0
K66R	DDI	>=0	53	0
K66R	D4T	>=0	55	0
K66R	ABC	>=0	47	0
K66R	>=0	NVP	4876	8	0.10	0.137
K66R	>=0	EFV	4514	6	0.10	0.446
K66R	>=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 66.

Mutation pattern data is not available for K66.

A complete summary of additional in vitro susceptibility data for viruses with K66 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 23 nonpolymorphic NRTI-resistance mutations shown to contribute decreased susceptibility to at least one NRTI. 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 66

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