<!--#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 184I606015-10-1010-10 184V606015-10-1010-10 41L551015151010 67N005151555 67E005101055 67G005101055 67STH005101055 70R001030151010 210W551015151010 215Y551545451515 215F551545451515 219QENRW005101055 40F5555555 44DA0000000 118I0000000 215CDEIVS00102020105 215NAL00102020105 65R303045-15456060 65N151525-10252525 65E00100101010 70GE101015-10151515 70TSNQ1010100101010 74I003000600 74V003000600 115F004500015 62V5555555 75I5555555 77L55101010105 116Y55101010105 151L10103030303010 151M15156060606015 66i30304545454545 67i30304545454545 68i30304545454545 69i30304545454545 70i30304545454545 71i30304545454545 66d15153030303030 67d15153030303030 68d15153030303030 69d1515150151515 70d1515150151515 71d1515150151515 69D000010300 69N00055100 69G0010010105 75M0001040150 75T0010060300 75S000010100 75A000010100 75L000010100 348I000101000
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
3444
B
23322
C
8513
D
1288
F
695
G
1370
AE
5379
AG
2725
 
A
175
B
4120
C
451
D
126
F
82
G
145
AE
333
AG
76
69 T S 0.6 S 0.7 S 1.1 S 0.5 I 0.6 S 0.7 N 0.8
S 0.6
  N 3.0
S 1.2
A 0.6
D 0.6
P 0.6
D 4.6
N 4.3
S 1.3
ins 0.5
N 2.7
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 2.8
S 2.2
A 0.6
I 0.6
ins 0.6
S 2.7
N 2.7
D 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.
MutationNRTINNRTINumSeqNumMut% Mutantp
T69ins00485410  
T69ins>=1>=0197312261.100.000
T69insAZT>=04510  
T69insDDI>=0530  
T69insD4T>=0550  
T69insABC>=0460  
T69insD4T+3TC>=0297830.100.000
T69insAZT+3TC>=0213010.000.022
T69insD4T+DDI>=046420.400.000
T69insAZT+DDI>=051320.300.000
T69insABC+3TC>=02300  
T69insTDF+3TC>=02830  
T69insTDF+FTC>=01490  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69A00485411300.20 
T69A>=1>=0197311020.500.000
T69AAZT>=045110.200.787
T69ADDI>=0530  
T69AD4T>=0550  
T69AABC>=0460  
T69AD4T+3TC>=02978371.200.000
T69AAZT+3TC>=0213070.300.752
T69AD4T+DDI>=046451.000.004
T69AAZT+DDI>=051371.300.000
T69AABC+3TC>=02300  
T69ATDF+3TC>=02830  
T69ATDF+FTC>=01490  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69D0048541160.00 
T69D>=1>=01973113066.600.000
T69DAZT>=045181.700.000
T69DDDI>=05311.800.000
T69DD4T>=05511.800.001
T69DABC>=04612.100.000
T69DD4T+3TC>=02978571.900.000
T69DAZT+3TC>=02130291.300.000
T69DD4T+DDI>=046471.500.000
T69DAZT+DDI>=0513203.800.000
T69DABC+3TC>=023010.400.137
T69DTDF+3TC>=028331.000.000
T69DTDF+FTC>=014910.600.049
MutationNRTINNRTINumSeqNumMut% Mutantp
T69E00485410  
T69E>=1>=019731170.000.000
T69EAZT>=04510  
T69EDDI>=0530  
T69ED4T>=0550  
T69EABC>=0460  
T69ED4T+3TC>=0297810.000.058
T69EAZT+3TC>=0213010.000.022
T69ED4T+DDI>=04640  
T69EAZT+DDI>=05130  
T69EABC+3TC>=02300  
T69ETDF+3TC>=02830  
T69ETDF+FTC>=01490  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69G004854110.00 
T69G>=1>=019731400.200.000
T69GAZT>=04510  
T69GDDI>=0530  
T69GD4T>=0550  
T69GABC>=0460  
T69GD4T+3TC>=0297820.000.001
T69GAZT+3TC>=021300  
T69GD4T+DDI>=04640  
T69GAZT+DDI>=05130  
T69GABC+3TC>=02300  
T69GTDF+3TC>=02830  
T69GTDF+FTC>=01490  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69I0048541500.10 
T69I>=1>=019731740.300.000
T69IAZT>=04510  
T69IDDI>=0530  
T69ID4T>=0550  
T69IABC>=0460  
T69ID4T+3TC>=02978100.300.001
T69IAZT+3TC>=0213010.000.653
T69ID4T+DDI>=04640  
T69IAZT+DDI>=051340.700.000
T69IABC+3TC>=02300  
T69ITDF+3TC>=02830  
T69ITDF+FTC>=01490  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69N00485412610.50 
T69N>=1>=01973110075.100.000
T69NAZT>=0451255.500.000
T69NDDI>=05335.600.000
T69ND4T>=0550  
T69NABC>=0460  
T69ND4T+3TC>=029781404.700.000
T69NAZT+3TC>=02130803.700.000
T69ND4T+DDI>=046461.200.060
T69NAZT+DDI>=0513214.000.000
T69NABC+3TC>=023052.100.004
T69NTDF+3TC>=028372.400.000
T69NTDF+FTC>=014921.300.436
MutationNRTINNRTINumSeqNumMut% Mutantp
T69P0048541260.00 
T69P>=1>=019731240.100.005
T69PAZT>=04510  
T69PDDI>=0530  
T69PD4T>=0550  
T69PABC>=0460  
T69PD4T+3TC>=0297840.100.167
T69PAZT+3TC>=0213040.100.042
T69PD4T+DDI>=046410.200.627
T69PAZT+DDI>=05130  
T69PABC+3TC>=023010.400.295
T69PTDF+3TC>=02830  
T69PTDF+FTC>=01490  
MutationNRTINNRTINumSeqNumMut% Mutantp
T69S00485414510.90 
T69S>=1>=0197311850.900.950
T69SAZT>=045191.900.036
T69SDDI>=0530  
T69SD4T>=05511.801.000
T69SABC>=0460  
T69SD4T+3TC>=02978230.700.441
T69SAZT+3TC>=02130221.000.709
T69SD4T+DDI>=046440.800.924
T69SAZT+DDI>=051350.900.903
T69SABC+3TC>=023041.700.352
T69STDF+3TC>=02830  
T69STDF+FTC>=014942.600.072
MutationNRTINNRTINumSeqNumMut% Mutantp
T69del004854110.00 
T69del>=1>=019731450.200.000
T69delAZT>=04510  
T69delDDI>=0530  
T69delD4T>=0550  
T69delABC>=0460  
T69delD4T+3TC>=02978290.900.000
T69delAZT+3TC>=021300  
T69delD4T+DDI>=046410.200.000
T69delAZT+DDI>=05130  
T69delABC+3TC>=02300  
T69delTDF+3TC>=028341.400.000
T69delTDF+FTC>=01490  
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
D4T
foldn
TDF
foldn
ABC
foldn
DDI
foldn
3TC
foldn
41L,67N,69D,184V,210W,215Y26546223.5221.8147.7212.12220020
41L,67N,69D,210W,215Y13192075.385.687.062.086.28
67N,69D,70R,184V,215F871341.941.035.441.942003
67N,69D,70R,215F85105112.5113.252.3111.2112.911
41L,67N,69D,74V,184V,210W,215Y762.711.910.617.912.212001
67N,69D,70R,184V685.521.221.813.811.122002
41L,67N,69D,70R,184V,215F671832.131.336.031.732003
41L,67N,69D,74V,210W,215Y634723.721.826.911.928.92
67N,69D,70R61      
41L,67N,69D,184V,210W53      
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.