Mutation ARV - Evidence

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MARVEL on RT mutations at position 67

HIVdb Algorithm: Comments & Scores

D67N contributes some degree of resistance to each of the NRTIs except 3TC and FTC. It usually occurs with mutations at positions 70 or 215. D67E/G occur in heavily treated patients but their precise effect on NRTI susceptibility is not known.
D67N contributes some degree of resistance to each of the NRTIs except 3TC and FTC. It usually occurs with mutations at positions 70 or 215. D67E/G occur in heavily treated patients but their precise effect on NRTI susceptibility is not known.
D67N contributes some degree of resistance to each of the NRTIs except 3TC and FTC. It usually occurs with mutations at positions 70 or 215.
Amino acid deletions (d) in this region occur uncommonly. They occur in combination with other NRTI mutations and contribute decreased susceptibility to each of the NRTIs.

Mutation	3TC	FTC	ABC	AZT	D4T	DDI	TDF
D67E	0	0	5	10	10	5	0
D67G	0	0	8	15	12	8	5
D67H	0	0	5	5	5	5	5
D67N	0	0	8	15	12	8	5
D67S	0	0	5	5	5	5	5
D67T	0	0	5	5	5	5	5
D67del	15	15	25	30	30	25	15

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 67 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 3215	B 22174	C 7465	D 1180	F 684	G 1316	AE 3654	AG 2607	A 172	B 4055	C 303	D 126	F 99	G 142	AE 325	AG 75
67	D									N ¹⁴ S ^1.2	N ²⁴ G ^1.0 E ^0.5	N ¹³ G ^0.7	N ¹⁷	N ¹⁸	N ²⁸ G ^0.8	N ³⁹ E ^1.9	N ¹⁶ A ^1.4 G ^1.4
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
D67A	0	0	43802	12	0.00
D67A	>=1	>=0	17332	15	0.00	0.003
D67A	AZT	>=0	448	2	0.40	0.000
D67A	DDI	>=0	53	0
D67A	D4T	>=0	55	0
D67A	ABC	>=0	45	0
D67A	D4T+3TC	>=0	2274	0
D67A	AZT+3TC	>=0	2101	0
D67A	D4T+DDI	>=0	460	0
D67A	AZT+DDI	>=0	509	1	0.10	0.361
D67A	ABC+3TC	>=0	26	0
D67A	TDF+3TC	>=0	94	0
D67A	TDF+FTC	>=0	24	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
D67E	0	0	43802	5	0.00
D67E	>=1	>=0	17332	100	0.50	0.000
D67E	AZT	>=0	448	1	0.20	0.073
D67E	DDI	>=0	53	0
D67E	D4T	>=0	55	0
D67E	ABC	>=0	45	0
D67E	D4T+3TC	>=0	2274	3	0.10	0.001
D67E	AZT+3TC	>=0	2101	2	0.00	0.033
D67E	D4T+DDI	>=0	460	2	0.40	0.000
D67E	AZT+DDI	>=0	509	8	1.50	0.000
D67E	ABC+3TC	>=0	26	0
D67E	TDF+3TC	>=0	94	0
D67E	TDF+FTC	>=0	24	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
D67G	0	0	43802	25	0.00
D67G	>=1	>=0	17332	414	2.30	0.000
D67G	AZT	>=0	448	1	0.20	0.643
D67G	DDI	>=0	53	0
D67G	D4T	>=0	55	0
D67G	ABC	>=0	45	0
D67G	D4T+3TC	>=0	2274	54	2.30	0.000
D67G	AZT+3TC	>=0	2101	18	0.80	0.000
D67G	D4T+DDI	>=0	460	12	2.60	0.000
D67G	AZT+DDI	>=0	509	3	0.50	0.000
D67G	ABC+3TC	>=0	26	0
D67G	TDF+3TC	>=0	94	1	1.00	0.059
D67G	TDF+FTC	>=0	24	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
D67H	0	0	43802	2	0.00
D67H	>=1	>=0	17332	44	0.20	0.000
D67H	AZT	>=0	448	0
D67H	DDI	>=0	53	0
D67H	D4T	>=0	55	0
D67H	ABC	>=0	45	0
D67H	D4T+3TC	>=0	2274	2	0.00	0.003
D67H	AZT+3TC	>=0	2101	2	0.00	0.002
D67H	D4T+DDI	>=0	460	0
D67H	AZT+DDI	>=0	509	0
D67H	ABC+3TC	>=0	26	0
D67H	TDF+3TC	>=0	94	0
D67H	TDF+FTC	>=0	24	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
D67N	0	0	43802	21	0.00
D67N	>=1	>=0	17332	5396	31.10	0.000
D67N	AZT	>=0	448	64	14.20	0.000
D67N	DDI	>=0	53	5	9.40	0.000
D67N	D4T	>=0	55	5	9.00	0.000
D67N	ABC	>=0	45	2	4.40	0.000
D67N	D4T+3TC	>=0	2274	358	15.70	0.000
D67N	AZT+3TC	>=0	2101	305	14.50	0.000
D67N	D4T+DDI	>=0	460	93	20.20	0.000
D67N	AZT+DDI	>=0	509	201	39.40	0.000
D67N	ABC+3TC	>=0	26	3	11.50	0.000
D67N	TDF+3TC	>=0	94	1	1.00	0.037
D67N	TDF+FTC	>=0	24	2	8.30	0.000

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
D67S	0	0	43802	1	0.00
D67S	>=1	>=0	17332	37	0.20	0.000
D67S	AZT	>=0	448	0
D67S	DDI	>=0	53	0
D67S	D4T	>=0	55	0
D67S	ABC	>=0	45	0
D67S	D4T+3TC	>=0	2274	2	0.00	0.000
D67S	AZT+3TC	>=0	2101	3	0.10	0.000
D67S	D4T+DDI	>=0	460	0
D67S	AZT+DDI	>=0	509	1	0.10	0.002
D67S	ABC+3TC	>=0	26	0
D67S	TDF+3TC	>=0	94	0
D67S	TDF+FTC	>=0	24	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
D67T	0	0	43802	0
D67T	>=1	>=0	17332	17	0.00	0.000
D67T	AZT	>=0	448	0
D67T	DDI	>=0	53	0
D67T	D4T	>=0	55	0
D67T	ABC	>=0	45	0
D67T	D4T+3TC	>=0	2274	0
D67T	AZT+3TC	>=0	2101	1	0.00	0.030
D67T	D4T+DDI	>=0	460	0
D67T	AZT+DDI	>=0	509	1	0.10	0.000
D67T	ABC+3TC	>=0	26	0
D67T	TDF+3TC	>=0	94	0
D67T	TDF+FTC	>=0	24	0

Mutation	NRTI	NNRTI	NumSeq	NumMut	% Mutant	p
D67del	0	0	43802	0
D67del	>=1	>=0	17332	14	0.00	0.000
D67del	AZT	>=0	448	0
D67del	DDI	>=0	53	0
D67del	D4T	>=0	55	0
D67del	ABC	>=0	45	0
D67del	D4T+3TC	>=0	2274	0
D67del	AZT+3TC	>=0	2101	0
D67del	D4T+DDI	>=0	460	0
D67del	AZT+DDI	>=0	509	0
D67del	ABC+3TC	>=0	26	0
D67del	TDF+3TC	>=0	94	0
D67del	TDF+FTC	>=0	24	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 67.

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 D67 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with D67 (not just the top 10 most frequent patterns) can be found at this page.

Mutation Patterns	Number of Sequences	AZT fold_n	D4T fold_n	TDF fold_n	ABC fold_n	DDI fold_n	3TC fold_n
67N,70R,184V	921	3.7₂₄	1.4₂₄	1.0₁₈	4.4₂₃	1.5₂₄	200₂₄
41L,67N,184V,210W,215Y	551	30₄₀	2.8₄₀	1.5₃₁	6.5₃₃	2.1₄₀	200₃₉
41L,67N,210W,215Y	515	880₁₉	4.2₁₉	4.8₁₅	6.4₁₆	1.9₁₉	5.3₁₉
67N,70R	485	30₁₈	1.8₁₈	2.3₁₅	1.9₁₆	1.1₁₈	2.0₁₈
67N,70R,184V,215F	306	7.7₇	1.8₇	1.0₄	5.5₇	1.7₇	200₇
41L,67N,69D,184V,210W,215Y	265	46₂₂	3.5₂₂	1.8₁₄	7.7₂₁	2.1₂₂	200₂₀
67N,70R,215F	264	91₁₄	2.1₁₄	2.4₁₃	2.3₁₃	1.3₁₄	3.3₁₄
41L,67N,74V,184V,210W,215Y	227	12₁₃	3.2₁₃	1.1₁₃	9.6₁₁	2.5₁₃	200₁₂
67N	183	1.2₆	1.1₆	1.0₄	0.9₅	1.1₆	2.1₆
41L,67N,70R,184V,215F	166	59₁₇	2.3₁₇	2.4₁₂	6.1₁₇	1.9₁₇	200₁₆
Footnote: Mutation patterns were defined by the presence or absence of major NRTI 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 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.

Genotype-clinical outcome correlation

Studies correlating baseline genotype and virological response to an ARV therapy with or without mutations at 67.

Reference	Previous NRTI	Follow-up NRTI	Other Rx	No.Pts	Weeks	Effect of baseline mutations on response
Katlama(2000)	>=2 NRTIs, (rare PI, NNRTI)	Addition of ABC	None	92	16-48	This study includes a subset of patients in the above analysis. M184V did not preclude an antiviral response. At week 16, 16/25 with M184V had RNA <=400 or RNA decrease of >=1 log.
Brun-Vezinet(2003)	NRTI, PI, NNRTI	ABC as part of a new HAART regimen	OB	175	12	RNA decrease was -0.2 logs, -0.7 logs, and -1.6 logs in persons containing 5-6, 4, or <4 mutations at the following positions: 41, 67, 210, 215, 74, and 184.
Lanier(2004)	>=2 NRTIs, (rare PI, NNRTI)	Addition of ABC	None	166	4	Meta-analysis of 5 intensification studies. Data on concomitant NNRTIs and PIs are not available. Median baseline RNA was 3.9 logs. 151/166 pts had >=1 NRTI mutation (usually TAMs and M184V). RNA decrease with (i) M184V alone >= 0.74 logs; (ii) 1 TAM >= 0.56 logs; (iii) M184V + 1 TAM >= 0.95 logs; (iv) 2-3 TAMs or 2 TAMs+ M184V >= ~0.35 logs; (v) M184V + 3 TAMs >= 0.18 logs; (vi) 4 TAMs >= 0.36 logs.
Winters(2003)	NRTI	NRTI change	NFV, EFV, NFV/EFV	104	16-48	In pts with isolates containing M184V substitution of ddI for 3TC was associated with a decreased risk of virologic failure (confirmed RNA >2000)
Frank(2004)	0, 1, and 2 NRTIs	ddI	Hydroxy-urea	134	24	Hydroxyurea + ddI led to a greater RNA decrease than ddI alone at week 8 (~1.8 vs 0.8 logs). The combination was associated with a sustained response ~1.2-1.6 logs at week 24. At week 8, there was a greater reduction in RNA in the NRTI-na�ve group (1.7 vs 1.2 logs) but there was little difference in response between those with M184V (1.2 logs in 18 3TC-experienced patients with M184V vs 1.4 logs in 61 3TC-na�ve patients).
Molina(2005)	NRTI, PI, NNRTI	Addition of ddI	None	109	4	Median overall response was 0.6 log RNA decrease. M184V alone >= 0.8 log RNA decrease. Pts with 0-1 TAMs >= 0.8-1.0 log RNA decrease (n=40); 2 TAMs >= 0.7 log RNA decrease (n=10); 3 TAMs >= 0.5 log RNA decrease (n=25); 4 TAMs >= 0.2 log RNA decrease (n=21). Median log RNA decrease in the presence of L74V (n=9) was 0.1 logs.
Sproat(2005)	NRTI, PI, NNRTI	ddI as part of a new HAART regimen	OB	281	4-48	Observational study. Overall RNA decrease was 1.2, 1.0, 0.8, and 0.8 at weeks 4, 12, 24, and 48. There was no significant difference in RNA response between the 105 pts with and the 176 pts without M184V.
De Luca(2007)	NRTI (including ddI in 76%) +/- NNRTI +/- PI	ddI as part of a new HAART regimen	OB	485	12	M41L, E44D/A/G, T69D/S/N/A, L210W, T215Y or T215 revertants, and L228H/R were associated with a reduced RNA decrease. D123E/N/G/S was associated with improved virological response. The following weighted score was derived: (M41L x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y revertants + L228H/R - D123E/N/G/S. Relative to those with a score <=0, those with a score of 1 to 3 had a 0.34 decreased log RNA response and those with a score >=4 had a 0.68 decreased RNA log response.
Barrios(2003)	NRTI, PI, NNRTI	TDF as part of a new HAART regimen	OB	153	24	Observational study. The presence of 41L, 210W, and 215Y were inversely associated with RNA response.
Masquelier(2004)	NRTI, PI, NNRTI	TDF as part of a new HAART regimen	OB	161	12	Observational study. The strongest association with RNA decrease was the set of the 7 mutations: M41L, E44D, D67N, T69D/N/S, L74V, L210W, and T215Y/F : (i) <3 mutations >= median RNA reduction of -1.3 logs; (ii) 3-5 mutations >= median RNA reduction of 0.8 logs; (iii) >=6 mutations >= median increase of 0.1 logs. K65R and T69ins were not included because although they cause phenotypic resistance, there were insufficient pts with these mutations.
Miller(2004)	NRTI, PI, NNRTI	Addition of TDF	None	222	24-48	Among pts receiving TDF, there was a mean 0.6 log RNA decrease at week 24 by ITT. Pts with 215Y/F alone had a 0.7 log RNA decrease. Pts with M41L+L210W + T215Y had a 0.2 log RNA decrease. Mutations at positions 67, 70, and 219 did not appear to affect response. K65R was present at baseline in 6 pts and was associated with lack of response. M184V was associated with a modest but significant improved response particularly in the absence of TAMs.
Abbreviations: OB - optimized background; TAM - thymidine analogue mutation (Type I: M41L, L210W, T215Y; Type II: D67N, K70R, T215F, K219Q/E;); References: Katlama C., Clotet B., Plettenberg A., Jost J., Arasteh K., Bernasconi E., Jeantils V., Cutrell A., Stone C., Ait-Khaled M., Purdon S. The role of abacavir (ABC, 1592) in antiretroviral therapy-experienced patients: results from a randomized, double-blind, trial. CNA3002 European Study Team. AIDS. 2000 May 5;14(7):781-9. Brun-Vezinet F., Descamps D., Ruffault A., Masquelier B., Calvez V., Peytavin G., Telles F., Morand-Joubert L., Meynard J.L., Vray M., Costagliola D. Clinically relevant interpretation of genotype for resistance to abacavir. AIDS. 2003 Aug 15;17(12):1795-802. Lanier E.R., Ait-Khaled M., Scott J., Stone C., Melby T., Sturge G., St Clair M., Steel H., Hetherington S., Pearce G., Spreen W., Lafon S. Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults harbouring HIV-1 with specific patterns of resistance to nucleoside reverse transcriptase inhibitors. Antivir Ther. 2004 Feb;9(1):37-45. Winters M.A., Bosch R.J., Albrecht M.A., Katzenstein D.A. Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside reverse-transcriptase inhibitor-experienced patients. J Infect Dis. 2003 Aug 15;188(4):537-40. Frank I., Bosch R.J., Fiscus S., Valentine F., Flexner C., Segal Y., Ruan P., Gulick R., Wood K., Estep S., Fox L., Nevin T., Stevens M., Eron J.J. Jr. Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307. AIDS Res Hum Retroviruses. 2004 Sep;20(9):916-26. Molina J.M., Marcelin A.G., Pavie J., Heripret L., De Boever C.M., Troccaz M., Leleu G., Calvez V.. Didanosine in HIV-1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial. J Infect Dis. 2005 Mar 15;191(6):840-7. Sproat M., Pozniak A.L., Peeters M., Winters B., Hoetelmans R., Graham N.M., Gazzard B.G. The influence of the M184V mutation in HIV-1 reverse transcriptase on the virological outcome of highly active antiretroviral therapy regimens with or without didanosine. Antivir Ther. 2005;10(2):357-61. De Luca A., Giambenedetto S.D., Trotta M.P., Colafigli M., Prosperi M., Ruiz L., Baxter J., Clevenbergh P., Cauda R., Perno C.F., Antinori A. Improved interpretation of genotypic changes in the HIV-1 reverse transcriptase coding region that determine the virological response to didanosine. J Infect Dis. 2007 Dec 1;196(11):1645-53. Barrios A., de Mendoza C., Martin-Carbonero L., Ribera E., Domingo P., Galindo M.J., Galvez J., Estrada V., Dalmau D., Asensi V., Soriano V. Role of baseline human immunodeficiency virus genotype as a predictor of viral response to tenofovir in heavily pretreated patients. Clin Microbiol. 2003 Sep;41(9):4421-3. Masquelier B., Tamalet C., Montes B., Descamps D., Peytavin G., Bocket L., Wirden M., Izopet J., Schneider V., Ferre V., Ruffault A., Palmer P., Trylesinski A., Miller M., Brun-Vezinet F., Costagliola D. Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitor-experienced patients. Antivir Ther. 2004 Jun;9(3):315-23. Miller M.D., Margot N., Lu B., Zhong L., Chen S.S., Cheng A., Wulfsohn M. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis. 2004 Mar 1;189(5):837-46.

MARVEL on RT mutations at position 67

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