<!--#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 65


HIVdb Algorithm: Comments & Scores
  • K65R causes intermediate/high-level resistance to TDF, ddI, ABC and d4T (2 to 3-fold reduced susceptibility) and low to intermediate-level resistance to 3TC and FTC (5 to 7-fold reduced susceptibility). K65R increases susceptibility to AZT.
  • K65R causes intermediate/high-level resistance to TDF, ddI, ABC and d4T (2 to 3-fold reduced susceptibility) and low to intermediate-level resistance to 3TC and FTC (5 to 7-fold reduced susceptibility). K65R increases susceptibility to AZT. K65E is an extremely rare NRTI-selected mutation with markedly reduced replication fitness.
  • K65R causes intermediate/high-level resistance to TDF, ddI, ABC and d4T (2 to 3-fold reduced susceptibility) and low to intermediate-level resistance to 3TC and FTC (5 to 7-fold reduced susceptibility). K65R increases susceptibility to AZT. K65N is a rare mutation with effects on NRTI susceptibility that are similar but weaker to those of K65R.

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 65 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
25449
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
65 K          R 2.4 R 1.1 R 1.4 R 1.6 R 1.3 R 1.4 R 2.1 R 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
K65E0051661140.00 
K65E>=1>=021980280.100.000
K65EAZT>=045310.200.304
K65EDDI>=0530  
K65ED4T>=0550  
K65EABC>=0460  
K65ED4T+3TC>=0299720.000.494
K65EAZT+3TC>=0228320.000.307
K65ED4T+DDI>=046410.200.314
K65EAZT+DDI>=05780  
K65EABC+3TC>=02300  
K65ETDF+3TC>=03060  
K65ETDF+FTC>=018410.500.052
MutationNRTINNRTINumSeqNumMut% Mutantp
K65N0051661140.00 
K65N>=1>=021980270.100.000
K65NAZT>=045310.200.304
K65NDDI>=0530  
K65ND4T>=0550  
K65NABC>=0460  
K65ND4T+3TC>=0299790.300.000
K65NAZT+3TC>=0228310.000.862
K65ND4T+DDI>=04640  
K65NAZT+DDI>=05780  
K65NABC+3TC>=02300  
K65NTDF+3TC>=030630.900.000
K65NTDF+FTC>=018410.500.052
MutationNRTINNRTINumSeqNumMut% Mutantp
K65R0051661200.00 
K65R>=1>=0219807923.600.000
K65RAZT>=04530  
K65RDDI>=05335.600.000
K65RD4T>=0550  
K65RABC>=04648.600.000
K65RD4T+3TC>=029971374.500.000
K65RAZT+3TC>=02283150.600.000
K65RD4T+DDI>=0464296.200.000
K65RAZT+DDI>=057850.800.000
K65RABC+3TC>=0230156.500.000
K65RTDF+3TC>=030613945.400.000
K65RTDF+FTC>=0184189.700.000
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 65.
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 K65 obtained using other assays including the Antivirogram can be found here. A complete list of all mutation patterns with K65 (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
65R3330.5171.8142.4179.017
65R,184V2850.4161.2168.41620016
65R,151M615223.62111462
65R,115F,184V58    
65R,184I420.331.133.132003
65R,151M,184V34    
65R,74V31    
65R,69~27    
65R,115F270.321.825.821112
65R,70R,151M25    
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 65.

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.