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.

NNRTI Resistance Notes

Last updated on March 2, 2014

Major Non-Nucleoside RT Inhibitor (NNRTI) Resistance Mutations
 
  100 101 103 106 138 181 188 190 230
Cons L K K V E Y Y G M
NVP I EP NS AM CIV LCH ASE L
EFV I EP NS AM CIV LCH ASE L
ETR I EP     AGKQ CIV L ASE L
RPV I EP     AGKQ CIV L ASE L
The table lists the most common clinically significant NNRTI-resistance mutations. Mutations in bold red are associated with the highest levels of reduced susceptibility or virological response to the relevant NNRTI. Mutations in bold reduce NNRTI susceptibility or virological response. Mutations in plain text contribute to reduced susceptibility in combination with other NNRTI-resistance mutations.

V90I
V90I is a polymorphic accessory mutation, which occurs in about 2% of viruses from ARV-naive individuals depending upon subtype (range: 0.2% to 6.4%; http://hivdb.stanford.edu/cgi-bin/MutPrevBySubtypeRx.cgi). It is selected in vitro by EFV (1), ETR (1) and RPV (2). It is weakly selected in patients receiving NVP and EFV (3) and by RPV (4). V90I has a weight of 1.0 in the Tibotec GSS for ETR (5). Alone it causes little, if any, reduction in NNRTI susceptibility (6,7,8,9).

A98G
A98G is a nonpolymorphic accessory mutation selected in patients receiving NVP and EFV (http://hivdb.stanford.edu/cgi-bin/RTPosMutSummary.cgi)(3) and in vitro by NVP (10). It reduces NVP and EFV susceptibility by about 5-fold and 3-fold, respectively (11,12,13,14). It has a weight of 1.0 in the Tibotec GSS for ETR (5).

L100I/V
L100I is selected in vitro by EFV (15,16), ETR (17) and RPV (2,18). It is selected in patients receiving EFV (19,20), ETR (21,22), and RPV (4). L100I rarely occurs in isolation, but when it does it reduces NVP and EFV susceptibility about 5-fold and 10-fold, respectively (14). In combination with K103N, it causes >50-fold reduced susceptibility to NVP and EFV (19,11,12,23), >10-fold reduced susceptibility to RPV, and 5 to 10-fold reduced susceptibility to ETR (17,2,23,24,25). L100I has a weight of 2.0 in the Tibotec ETR GSS. L100V is a rare nonpolymorphic mutation associated with about a 10-fold reduction in susceptibility to EFV and a 5-fold reduction in susceptibility to NVP in site-directed mutagenesis studies (26). It is also possibly associated with reduced ETR and RPV susceptibility (13).

K101E/H/P/Q/R/N/A/T
K101E is a nonpolymorphic mutation selected in patients receiving each of the NNRTIs (19,20,27,4). K101E usually occurs in combination with other NNRTI-resistance mutations. Alone it reduces susceptibility to NVP by 3 to 10-fold, to EFV by 1 to 5-fold, and to ETR and RPV by about 2-fold (2,4,28,14). In combination with M184I, K101E reduces RPV susceptibility about 5-fold (4). K101E has a weight of 1.0 in the Tibotec ETR GSS.

K101H is a nonpolymorphic mutation selected in patients receiving NVP, EFV, and ETR (29,20,27). When it occurs in combination with other NNRTI-resistance mutations, K101H is associated with reduced susceptibility to NVP and EFV (14) and has a weight of 1.0 in the Tibotec ETR genotypic susceptibility scores.

K101P is a nonpolymorphic two base-pair mutation selected in patients receiving each of the NNRTIs (20,27,4). It reduces NVP, EFV, and RPV susceptibility by >50-fold and ETR susceptibility by ~5-fold (30,25,2,31,32,14). It has a weight of 2.5 in the Tibotec ETR genotypic susceptibility score.

K101Q is a minimally polymorphic accessory mutation weakly selected in patients receiving NVP and EFV (3). It appears to have minimal, if any, detectable effect on NNRTI susceptibility (3).

K101R is a polymorphic mutation that is not selected by NNRTIs (3). It has no effect on NNRTI susceptibility (3)

K101N/A/T are nonpolymorphic ARV-selected mutations (3,13). Their effects on NNRTI susceptibility are not known.

K103N/S/H/T/R/Q/E
K103N is a nonpolymorphic mutation selected in patients receiving NVP and EFV (19,33,34,20). It reduces NVP and EFV susceptibility by about 50 and 20-fold, respectively (11,35,36,12,14).

K103S is a nonpolymorphic two base-pair mutation selected by NVP and EFV. It usually occurs in samples from patients who previously had K103N (3,20). It causes intermediate to high-level resistance to these NNRTIs (37,12,14). Because K103S is a 2-bp change from the wildtype K, patients with K103S may be more likely to harbor K103N, which is just a 1-bp change from wildtype.

K103H is a rare nonpolymorphic mutation that causes high-level resistance (about 20-fold reduced susceptibility) to NVP and EFV (37).

K103T is a rare nonpolymorphic mutation that causes high-level (about 10-fold reduction in susceptibility) resistance to NVP. It has little, if any, effect on EFV susceptibility (37,38,13).

K103R is a polymorphic mutation that alone has no effect on NNRTI susceptibility. However, in combination with V179D (and possibly V179E), K103R reduces NVP and EFV susceptibility about 15-fold (30).

K103E/Q are rare mutations that do not appear to be selected by NNRTI treatment (3). They have not been associated with reduced susceptibility to any of the NNRTIs.

V106A/M/I
V106A is a nonpolymorphic mutation selected primarily by NVP (39,40,20). It causes about a 50-fold reduction in NVP susceptibility and about a 5-fold reduction in EFV susceptibility (41,42,32,43,13,14). Together, V106A and F227L cause high-level resistance to both NVP and EFV (14).

V106M is a nonpolymorphic mutation selected primarily by EFV and NVP. It is particularly common in subtype C viruses (44,45,46,47,48,49,50). It causes >30-fold reduced susceptibility to NVP and EFV (13,14).

V106I is a polymorphic accessory NNRTI-selected mutation (3). In combination with V179D, it causes low-level resistance to NVP, EFV, ETR, and probably RPV (51). It has a weight of 1.5 in the Tibotec ETR genotypic susceptibility score (52). Alone it appears to have little, if any effect on NNRTI susceptibility or the virological response to an NNRTI-containing regimen (8,7).

V108I
V108I is a relatively nonpolymorphic accessory mutation that is selected in vitro by NVP (10) and EFV (15) and in patients receiving NVP (20,40), EFV (20,36) and ETR (27). It reduces NVP and EFV susceptibility by about 2-fold (53,11) but does not appear to reduce susceptibility to ETR or RPV (14,8,7).

I132M/L
I132M is an extremely rare nonpolymorphic mutation that reduces NVP and EFV susceptibility in biochemical assays (54,55). It has not been shown to be selected by any of the NNRTIs. I132L is a more common, nonpolymorphic NNRTI-selected mutation (3) that has not been well studied.

E138A/G/K/Q/R
E138K is a nonpolymorphic mutation that is selected in a high proportion of patients receiving RPV (4). Alone it reduces RPV susceptibility 2 to 3-fold; in combination with the NRTI-resistance mutation M184I, it reduces RPV susceptibility by about 5-fold (4,56,57). The combination of E138K and M184I appears sufficient to cause virological failure on an RPV-containing regimen (4). E138K is also selected in patients receiving ETR (27) and reduces ETR susceptibility about 2-fold about (58,59,14).

E138A is a polymorphic mutation that ranges in prevalence from 0.5% in subtype B viruses to 5% in subtype C viruses (http://hivdb.stanford.edu/cgi-bin/MutPrevBySubtypeRx.cgi). It is weakly selected by ETR and RPV. It reduces ETR (58,60) and RPV (57) susceptibility about 2-fold. It has a weight of 1.5 in the Tibotec ETR GSS (5). According to the RPV package insert (52), the presence of E138A prior to therapy may reduce the antiviral activity of RPV.

E138Q/G are nonpolymorphic accessory mutations frequently selected by ETR (27,58) and/or RPV (4) and occasionally selected by NVP and EFV (3). These mutations are associated with 2 to 3-fold reduced susceptibility to ETR and RPV (58,60,14). E138R is a rare nonpolymorphic accessory mutation selected in vitro by RPV. It is associated with 2 to 3-fold reduced susceptibility to ETR and RPV (2).

V179D/E/F/I/L/T
V179D is a polymorphic accessory mutation occasionally selected in patients receiving EFV. It reduces NVP and EFV susceptibility by 2 to 5-fold (14) but the clinical significance of this reduction is not known. It reduces susceptibility to ETR and RPV 2 to 3-fold (32,14). The combination of V179D and K103R act synergistically, reducing NVP and EFV susceptibility >10-fold (30). The combination of V179D and V106I also appear to act synergistically to reduce NVP and EFV susceptibility (51). V179D has a weight of 1.0 the Tibotec ETR genotypic susceptibility score (5).

V179E is a nonpolymorphic mutation weakly selected by NVP and EFV (3). It is associated with low-level resistance to NVP, EFV, and ETR (3,32,13,60).

V179F is a nonpolymorphic accessory mutation that usually emerges in combination with Y181C. It is one of the most common mutations emerging in patients receiving ETR (27,22). Alone it does not reduce NNRTI susceptibility, but the combination of V179F and Y181C confers high-level resistance to ETR and RPV (>10-fold reduced susceptibility) (2,5,13).

V179I is a polymorphic mutation that is frequently selected in patients receiving ETR and RPV (27,22,4). It has little, if any, effect on NNRTI susceptibility (8).

V179T is a rare nonpolymorphic mutation that is infrequently selected in patients receiving NNRTIs. It appears to be associated with minimal reductions in ETR and RPV susceptibility (60,14,2,5,13). It has a weight of 1.0 in the Tibotec ETR GSS.

V179L is a rare nonpolymorphic mutation that is infrequently selected in patients NVP, EFV, and RPV (3,52). Its effect on NNRTI susceptibility is not well studied (60). It is listed as an RPV-associated drug-resistance mutation in the RPV package insert (52).

Y181C/I/V/F/S/G
Y181C is a nonpolymorphic mutation selected in vitro by NVP (61,10), EFV (15), ETR (17), and RPV (2). It is selected in vivo primarily by NVP (20), ETR (27), and RPV (4). It causes >50-fold reduced susceptibility to NVP (11,62,5), about 5-fold reduced susceptibility to ETR (5,32,63), about 3-fold reduced susceptibility to RPV (4), and about 2-fold reduced susceptibility to EFV (11). Although Y181C itself reduces EFV susceptibility by only 2-fold, it is associated with a reduced response to treatment with an EFV-containing regimen. This is presumably because other NNRTI-resistance mutations are often present as minority variants in studies in which EFV was used following NVP treatment. Y181C has a weight of 2.5 in the Tibotec ETR GSS (5).

Y181I/V are 2-base pair nonpolymorphic mutations selected by NVP (3) and ETR (27). Y181I/V cause high-level resistance to NVP (>50-fold reduced susceptibility) and a 10 to 15-fold reduction in susceptibility to ETR (52) and RPV (2). Y181I/V each have a weight of 3.0 in the Tibotec ETR GSS (5).

Y181F/S/G are rare nonpolymorphic NNRTI-associated mutations that are usually present as part of an electrophoretic mixture (3). They likely represent transitional mutations between Y and I or V or possibly partial revertant mutations.

Y188L/C/H/F
Y188L is a nonpolymorphic 2-base pair mutation selected by NVP and EFV (20,19). It confers high-level resistance (>50-fold reduction in susceptibility) to NVP and EFV (36,11,53,64,12). It is also associated with about 5-fold reduced susceptibility to RPV (65,66) (3) and minimally reduced susceptibility to ETR (67,13)

Y188C is an uncommon nonpolymorphic mutation selected by NVP and EFV. It confers high-level resistance to NVP (>50-fold decreased susceptibility) and EFV (~20-fold reduced susceptibility) (3,20). It has not been shown to be selected by or to reduce susceptibility to ETR or RPV.

Y188H is an uncommon nonpolymorphic mutation selected by NVP and EFV. It confers about 10-fold reduced susceptibility to NVP and about 5-fold reduced susceptibility to EFV (3,20,12). There is no evidence that it is selected by or confers decreased susceptibility to ETR or RPV.

Y188F is a rare nonpolymorphic NNRTI-associated mutations that is usually present as part of an electrophoretic mixture (3). It is likely to represent a transitional mutation between Y and L or possibly a partial revertant mutation.

G190A/S/E/Q/C/T/V
G190A is a nonpolymorphic mutation selected by NVP and EFV (20,19,33). Alone G190A reduces NVP susceptibility >50-fold and EFV susceptibility 5 to 10-fold (11,68,12). It has a weight of 1.0 in the Tibotec ETR GSS (5) but does not appear to be selected by ETR and RPV or to reduce their antiviral activity (13,3,60,14).

G190S is a nonpolymorphic mutation selected by NVP and EFV. G190S causes >50-fold decreased susceptibility to NVP and EFV (11,68,12). It has a weight of 1.5 in the Tibotec ETR GSS (5), but it does not appear to be selected by ETR or RPV or to reduce their antiviral activity (13,3,60,14).

G190E/Q are uncommon nonpolymorphic mutations selected in patients receiving EFV (3,20,19,69) and in cell culture with ETR and RPV (2,1). G190E/Q cause high-level resistance to NVP, EFV, and intermediate/high-level resistance to ETR and RPV (17,2,60,13,14).

G190C/T/V are extremely rare nonpolymorphic NNRTI-selected mutations that confer high-level resistance to NVP and EFV (68). Their effects on ETR and RPV susceptibility are not known.

H221Y
H221Y is a nonpolymorphic accessory NNRTI-selected mutation that usually occurs in combination with Y181C (29,20). Alone it has minimal detectable effects on NNRTI susceptibility (14). It is frequently selected in patients receiving RPV (4,52).

P225H
P225H is a nonpolymorphic accessory mutation selected by EFV that usually occurs in combination with K103N (19,3,69,70). Together K103N and P225H cause >50-fold reduction in susceptibility to NVP and EFV (11,36).

F227L/C
F227L is a nonpolymorphic mutation selected by NVP and EFV that usually occurs in combination with V106A (20,41). The combination of V106A and F227L confers high-level resistance to NVP and EFV (3,12).

F227C is an extremely rare mutation selected in vitro by ETR and RPV and in patients receiving RPV (4). It causes high-level resistance (>10-fold reduced susceptibility) to each of the NNRTIs when present in combination with other NNRTI-resistance mutations (67,38,14).

M230L/I
M230L is an uncommon nonpolymorphic mutation selected in patients receiving EFV, NVP and RPV (29,6) and by ETR and RPV in vitro (17,2). M230L confers intermediate to high-level resistance to each of the NNRTIs (71,17,2,72,14).

M230I is an extremely rare mutation selected in vitro by RPV (2). Its effects on NNRTI susceptibility have not been well studied.

L234I
L234I is an uncommon nonpolymorphic accessory mutation selected in patients receiving NVP and EFV (3). It is also select in vitro by ETR (17). Its effect on susceptibility to the current NNRTIs is not known.

P236L
P236L is a rare nonpolymorphic mutation associated with high-level resistance to delavirdine (73,74). It does not appear to reduce susceptibility to any other NNRTIs.

K238T/N
K238T is a nonpolymorphic mutation selected in patients receiving NVP and EFV (3,20). It often occurs in combination with K103N (20). It reduces susceptibility to NVP and EFV by about 5-fold (30,3) and possibly reduces susceptibility to ETR and RPV (13,60).

K238N is a nonpolymorphic accessory mutation that is selected by NVP and EFV. It is weakly associated with reduced susceptibility to these NNRTIs and possibly ETR (29,13,60).

Y318F
Y318F is a nonpolymorphic mutation infrequently selected in vivo by NVP and EFV (20) and in vitro by ETR (17). It reduces NVP susceptibility by about 5-fold but has little phenotypic effect on the remaining NNRTIs (75,17).

N348I
N348I is a nonpolymorphic accessory mutation selected by the NRTIs AZT and d4T and by NVP and EFV (76,77,78). Alone it reduces AZT susceptibility about 3-fold and NVP and EFV susceptibility by 3-fold and 2-fold, respectively (76,77,23,63)

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