<!--#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 70


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.
  • K70E/G cause low/intermediate-level resistance (2 to 3-fold reduced susceptibility) to TDF, ABC, DDI and possibly 3TC and FTC. K70E increases susceptibility to AZT.
  • K70R causes intermediate-level resistance to AZT and possibly low-level resistance to d4T and TDF.
  • K70R causes intermediate-level resistance to AZT and possibly low-level resistance to d4T and TDF. K70E/G cause low/intermediate-level resistance (2 to 3-fold reduced susceptibility) to TDF, ABC, DDI and possibly 3TC and FTC. K70E increases susceptibility to AZT. K70Q/N/S/T are rare nonpolymorphic NRTI-selected mutations that appear to have resistance profiles similar to K70E/G.

Mutation3TCFTCABCAZTD4TDDITDF
K70E101015-10151515
K70G101015-10151515
K70N1010100101010
K70Q1010100101010
K70R001030151010
K70S1010100101010
K70T1010100101010
K70del1515150151515
K70ins30304545454545
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 70 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
4192
B
27421
C
8709
D
1603
F
728
G
1593
AE
5640
AG
2957
 
A
205
B
4133
C
551
D
127
F
82
G
146
AE
330
AG
78
70 K          R 13
N 0.5
R 21 R 5.5 R 8.1
T 1.6
S 0.8
N 0.8
R 23 R 17
E 1.4
R 25 R 14
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
K70E0054747130.00 
K70E>=1>=0254781410.500.000
K70EAZT>=04520  
K70EDDI>=0530  
K70ED4T>=0550  
K70EABC>=0470  
K70ED4T+3TC>=03273170.500.000
K70EAZT+3TC>=0233510.000.920
K70ED4T+DDI>=046240.800.000
K70EAZT+DDI>=05770  
K70EABC+3TC>=028510.300.111
K70ETDF+3TC>=0374143.700.000
K70ETDF+FTC>=0352185.100.000
MutationNRTINNRTINumSeqNumMut% Mutantp
K70G00547470  
K70G>=1>=025478890.300.000
K70GAZT>=04520  
K70GDDI>=0530  
K70GD4T>=0550  
K70GABC>=0470  
K70GD4T+3TC>=0327320.000.000
K70GAZT+3TC>=023350  
K70GD4T+DDI>=04620  
K70GAZT+DDI>=057710.100.000
K70GABC+3TC>=02850  
K70GTDF+3TC>=037420.500.000
K70GTDF+FTC>=03520  
MutationNRTINNRTINumSeqNumMut% Mutantp
K70N0054747150.00 
K70N>=1>=025478600.200.000
K70NAZT>=04520  
K70NDDI>=0530  
K70ND4T>=05511.800.000
K70NABC>=0470  
K70ND4T+3TC>=0327370.200.000
K70NAZT+3TC>=0233530.100.036
K70ND4T+DDI>=046251.000.000
K70NAZT+DDI>=05770  
K70NABC+3TC>=02850  
K70NTDF+3TC>=037410.200.233
K70NTDF+FTC>=03520  
MutationNRTINNRTINumSeqNumMut% Mutantp
K70Q0054747130.00 
K70Q>=1>=025478530.200.000
K70QAZT>=04520  
K70QDDI>=0530  
K70QD4T>=0550  
K70QABC>=0470  
K70QD4T+3TC>=0327320.000.464
K70QAZT+3TC>=0233510.000.920
K70QD4T+DDI>=046210.200.261
K70QAZT+DDI>=05770  
K70QABC+3TC>=028510.300.111
K70QTDF+3TC>=037441.000.000
K70QTDF+FTC>=035241.100.000
MutationNRTINNRTINumSeqNumMut% Mutantp
K70R0054747380.00 
K70R>=1>=025478458617.900.000
K70RAZT>=045213329.400.000
K70RDDI>=05335.600.000
K70RD4T>=05559.000.000
K70RABC>=04724.200.000
K70RD4T+3TC>=0327333210.100.000
K70RAZT+3TC>=0233536015.400.000
K70RD4T+DDI>=04625311.400.000
K70RAZT+DDI>=057715226.300.000
K70RABC+3TC>=028531.000.000
K70RTDF+3TC>=0374123.200.000
K70RTDF+FTC>=035241.100.000
MutationNRTINNRTINumSeqNumMut% Mutantp
K70S005474710.00 
K70S>=1>=025478210.000.000
K70SAZT>=04520  
K70SDDI>=0530  
K70SD4T>=0550  
K70SABC>=0470  
K70SD4T+3TC>=0327310.000.235
K70SAZT+3TC>=0233510.000.135
K70SD4T+DDI>=04620  
K70SAZT+DDI>=05770  
K70SABC+3TC>=02850  
K70STDF+3TC>=03740  
K70STDF+FTC>=03520  
MutationNRTINNRTINumSeqNumMut% Mutantp
K70T0054747160.00 
K70T>=1>=025478800.300.000
K70TAZT>=04520  
K70TDDI>=0530  
K70TD4T>=0550  
K70TABC>=0470  
K70TD4T+3TC>=0327370.200.000
K70TAZT+3TC>=0233540.100.002
K70TD4T+DDI>=046210.200.341
K70TAZT+DDI>=05770  
K70TABC+3TC>=02850  
K70TTDF+3TC>=037430.800.000
K70TTDF+FTC>=035230.800.000
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 70.
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 K70 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with K70 (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
67N,70R,184V11443.7321.2264.53120050
70R,184V6970.8140.773.41520021
67N,70R59328231.9191.6212.132
70R4875.3151.3131.1161.223
67N,70R,184V,215F3817.771.045.572008
67N,70R,215F303102152.6142.5143.619
41L,67N,70R,184V,215F23059192.3136.11920027
41L,67N,70R,184V,215Y1527.861.545.462007
41L,67N,70R,215F14238785.553.694.313
41L,67N,70R,184V,210W,215Y1257682.566.9720012
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 70.

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.