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.
- 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.
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.
|Pos||WT||RTI Naive Persons|| ||NRTI (but no NNRTI) Treated Persons|
|| || || || || || || || || ||R 2.4 ||R 1.1 ||R 1.4 ||R 1.7 ||R 1.3 ||R 1.4 ||R 2.2 ||R 1.3 |
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 Patterns||Number of|
|65R,115F,184V||53|| || || || || || |
|65R,151M,184V||31|| || || || || || |
|65R,74V||30|| || || || || || |
|65R,69~||26|| || || || || || |
|65R,70R,151M||24|| || || || || || |
||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.|
|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.|