<!--#if expr="$title" --> <!--#echo var="title" --> <!--#else --> HIV Drug Resistance Database <!--#endif -->
Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

MARVEL on RT mutations at position 69


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.
  • T69D is a nonpolymorphic mutation that reduces susceptibility to ddI and possibly d4T.
  • T69G is a rare polymorphic mutation that usually occurs in viruses with a deletion at codon 67 and multiple NRTI-resistance mutations. It is associated with reduced susceptibility to ddI, d4T, ABC and possibly TDF.
  • T69N is a relatively non-polymorphic mutation weakly selected in patients receiving NRTIs. Their effects on NRTI susceptibility have not been well studied.
  • T69S/A/I/E are relatively non-polymorphic mutations weakly selected in patients receiving NRTIs. Their effects on NRTI susceptibility have not been well studied.

Mutation3TCFTCABCAZTD4TDDITDF
T69D000010300
T69G0010010105
T69N00055100
T69del1515150151515
T69ins30304545454545
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 69 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.

PosWTRTI Naive Persons NRTI (but no NNRTI) Treated Persons
A
3547
B
25466
C
8621
D
1320
F
723
G
1577
AE
5645
AG
2906
 
A
179
B
4133
C
461
D
127
F
82
G
146
AE
339
AG
78
69 T S 0.6 S 0.7 S 1.1 S 0.5 I 0.6 S 0.8 N 0.8
S 0.6
  N 2.9
S 1.2
A 0.6
D 0.6
P 0.6
D 4.7
N 4.3
S 1.3
ins 0.5
N 2.6
D 1.9
S 0.7
S 2.5
D 0.8
I 0.8
D 2.6
S 1.3
A 1.3
N 1.3
N 2.2
D 2.2
S 1.5
D 4.0
N 2.7
S 2.1
A 0.6
I 0.6
ins 0.6
S 2.6
N 2.6
D 1.3
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.
MutationNRTINNRTINumSeqNumMut% Mutantp
T69ins00516550  
T69ins>=1>=0219222331.000.000
T69insAZT>=04510  
T69insDDI>=0530  
T69insD4T>=0550  
T69insABC>=0460  
T69insD4T+3TC>=0299530.100.000
T69insAZT+3TC>=0228330.100.000
T69insD4T+DDI>=046420.400.000
T69insAZT+DDI>=057720.300.000
T69insABC+3TC>=02300  
T69insTDF+3TC>=03050  
T69insTDF+FTC>=02000  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69A00516551440.20 
T69A>=1>=0219221090.400.000
T69AAZT>=045110.200.827
T69ADDI>=0530  
T69AD4T>=0550  
T69AABC>=0460  
T69AD4T+3TC>=02995371.200.000
T69AAZT+3TC>=0228380.300.667
T69AD4T+DDI>=046451.000.006
T69AAZT+DDI>=057771.200.000
T69AABC+3TC>=02300  
T69ATDF+3TC>=03050  
T69ATDF+FTC>=02000  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69D0051655180.00 
T69D>=1>=02192213666.200.000
T69DAZT>=045181.700.000
T69DDDI>=05311.800.001
T69DD4T>=05511.800.001
T69DABC>=04612.100.000
T69DD4T+3TC>=02995571.900.000
T69DAZT+3TC>=02283321.400.000
T69DD4T+DDI>=046471.500.000
T69DAZT+DDI>=0577203.400.000
T69DABC+3TC>=023010.400.151
T69DTDF+3TC>=030530.900.000
T69DTDF+FTC>=020010.500.114
MutationNRTINNRTINumSeqNumMut% Mutantp
T69E00516550  
T69E>=1>=021922170.000.000
T69EAZT>=04510  
T69EDDI>=0530  
T69ED4T>=0550  
T69EABC>=0460  
T69ED4T+3TC>=0299510.000.050
T69EAZT+3TC>=0228310.000.023
T69ED4T+DDI>=04640  
T69EAZT+DDI>=05770  
T69EABC+3TC>=02300  
T69ETDF+3TC>=03050  
T69ETDF+FTC>=02000  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69G005165510.00 
T69G>=1>=021922410.100.000
T69GAZT>=04510  
T69GDDI>=0530  
T69GD4T>=0550  
T69GABC>=0460  
T69GD4T+3TC>=0299520.000.001
T69GAZT+3TC>=022830  
T69GD4T+DDI>=04640  
T69GAZT+DDI>=05770  
T69GABC+3TC>=02300  
T69GTDF+3TC>=03050  
T69GTDF+FTC>=02000  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69I0051655550.10 
T69I>=1>=021922840.300.000
T69IAZT>=04510  
T69IDDI>=0530  
T69ID4T>=0550  
T69IABC>=0460  
T69ID4T+3TC>=02995100.300.001
T69IAZT+3TC>=0228330.100.975
T69ID4T+DDI>=04640  
T69IAZT+DDI>=057740.600.000
T69IABC+3TC>=02300  
T69ITDF+3TC>=03050  
T69ITDF+FTC>=02000  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69N00516552720.50 
T69N>=1>=02192211185.000.000
T69NAZT>=0451255.500.000
T69NDDI>=05335.600.000
T69ND4T>=0550  
T69NABC>=0460  
T69ND4T+3TC>=029951404.600.000
T69NAZT+3TC>=02283853.700.000
T69ND4T+DDI>=046461.200.053
T69NAZT+DDI>=0577223.800.000
T69NABC+3TC>=023052.100.003
T69NTDF+3TC>=030572.200.000
T69NTDF+FTC>=020021.000.665
MutationNRTINNRTINumSeqNumMut% Mutantp
T69P0051655270.00 
T69P>=1>=021922280.100.001
T69PAZT>=04510  
T69PDDI>=0530  
T69PD4T>=0550  
T69PABC>=0460  
T69PD4T+3TC>=0299540.100.155
T69PAZT+3TC>=0228340.100.051
T69PD4T+DDI>=046410.200.614
T69PAZT+DDI>=05770  
T69PABC+3TC>=023010.400.285
T69PTDF+3TC>=03050  
T69PTDF+FTC>=02000  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69S00516554750.90 
T69S>=1>=0219222050.900.872
T69SAZT>=045191.900.034
T69SDDI>=0530  
T69SD4T>=05511.801.000
T69SABC>=0460  
T69SD4T+3TC>=02995230.700.453
T69SAZT+3TC>=02283220.900.916
T69SD4T+DDI>=046440.800.909
T69SAZT+DDI>=057750.800.929
T69SABC+3TC>=023041.700.341
T69STDF+3TC>=03050  
T69STDF+FTC>=020042.000.221
MutationNRTINNRTINumSeqNumMut% Mutantp
T69del005165510.00 
T69del>=1>=021922480.200.000
T69delAZT>=04510  
T69delDDI>=0530  
T69delD4T>=0550  
T69delABC>=0460  
T69delD4T+3TC>=02995290.900.000
T69delAZT+3TC>=0228310.000.145
T69delD4T+DDI>=046410.200.000
T69delAZT+DDI>=05770  
T69delABC+3TC>=02300  
T69delTDF+3TC>=030541.300.000
T69delTDF+FTC>=02000  
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 69.
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 T69 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with T69 (not just the top 10 most frequent patterns) can be found at this page.

Mutation PatternsNumber of
Sequences
AZT
foldn
TDF
foldn
ABC
foldn
3TC
foldn
41L,67N,69D,184V,210W,215Y31943281.8197.82620025
41L,67N,69D,210W,215Y171672153.9156.4126.816
67N,69D,70R,184V,215F971171.055.172006
67N,69D,70R,215F91104122.662.2123.212
41L,67N,69D,70R,184V,215F873561.356.562006
41L,67N,69D,74V,184V,210W,215Y852.710.617.912001
67N,69D,70R,184V722.831.223.722003
41L,67N,69D,184V,210W64    
41L,67N,69D,74V,210W,215Y634721.826.918.92
67N,69D,70R63    
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 69.

ReferencePrevious NRTIFollow-up NRTIOther RxNo.PtsWeeksEffect of baseline mutations on response
Katlama(2000)>=2 NRTIs, (rare PI, NNRTI)Addition of ABCNone9216-48This 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, NNRTIABC as part of a new HAART regimenOB17512RNA 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 ABCNone1664Meta-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)NRTINRTI changeNFV, EFV, NFV/EFV10416-48In 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 NRTIsddIHydroxy-urea13424Hydroxyurea + 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, NNRTIAddition of ddINone1094Median 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, NNRTIddI as part of a new HAART regimenOB2814-48Observational 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 +/- PIddI as part of a new HAART regimenOB48512M41L, 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, NNRTITDF as part of a new HAART regimenOB15324Observational study. The presence of 41L, 210W, and 215Y were inversely associated with RNA response.
Masquelier(2004)NRTI, PI, NNRTITDF as part of a new HAART regimenOB16112Observational 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, NNRTIAddition of TDFNone22224-48Among 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.