HIVdb version 8.1.1 (last updated 2016-09-23)

NNRTI Resistance Notes

(PI · NRTI · INSTI)

Major Non-Nucleoside RT Inhibitor (NNRTI) Resistance Mutations


Consensus
100
L
101
K
103
K
106
V
138
E
181
Y
188
Y
190
G
230
M
NVPIEPNSAMCIVLCHASEL
EFVIEPNSAMCIVLCHASEL
ETRIEPAGKQCIVLASEL
RPVIEPAGKQCIVLASEL

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, depending on subtype, occurs in 0.2% to 6% of viruses ARV-naive patients. It is selected in vitro by EFV (1), ETR (1) and RPV (2). It is weakly selected in patients receiving NVP, EFV, and RPV (3,4). V90I has a weight of 1.0 in the Tibotec genotypic susceptibility score for ETR (5). Alone it causes little, if any, reduction in NNRTI susceptibility (6,7,8,9,10,11).

A98G

A98G is a relatively nonpolymorphic accessory mutation, which depending on subtype, occurs in 0.1% to 0.6% of ARV-naive patients. It is selected in patients receiving NVP and EFV. It reduces NVP, EFV, and RPV susceptibility by about 2- to 3-fold (12,13,14,10,11). It has a weight of 1.0 in the Tibotec genotypic susceptibility score for ETR (5).

L100I

L100I is selected in patients receiving EFV (15,16), ETR (17,18), and RPV (4). It is also selected in vitro by EFV (19,20), ETR (21) and RPV (2,22). L100I rarely occurs in isolation, but when it does it reduces NVP and EFV susceptibility about 5-fold and 10-fold, respectively (10). In combination with K103N, it causes >50-fold reduced susceptibility to NVP and EFV (15,12,13,23), >10-fold reduced susceptibility to RPV, and 5 to 10-fold reduced susceptibility to ETR (21,2,23,24,25). L100I has a weight of 2.0 in the Tibotec ETR genotypic susceptibility score.

L100V is an extremely rare nonpolymorphic mutation. In site-directed mutagenesis studies, it reduced NVP and EFV susceptibility 5-fold and 10-fold, respectively (26). It is also possibly associated with reduced ETR and RPV susceptibility (14).

K101E/H/P/Q/R/N

K101E is a nonpolymorphic mutation selected in patients receiving each of the NNRTIs (15,16,27,4). 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 (2,4,28,10). K101E has a weight of 1.0 in the Tibotec ETR genotypic susceptibility score.

K101P is a nonpolymorphic two base-pair mutation selected in patients receiving each of the NNRTIs (16,27,4). It reduces NVP, EFV, and RPV susceptibility by >50-fold and ETR susceptibility by ~5-fold (29,25,2,30,31,10). It has a weight of 2.5 in the Tibotec ETR genotypic susceptibility score.

K101H is a nonpolymorphic mutation selected in patients receiving NVP, EFV, and ETR (32,16,27). When it occurs in combination with other NNRTI-resistance mutations, K101H is associated with reduced susceptibility to NVP and EFV (10) and has a weight of 1.0 in the Tibotec ETR genotypic susceptibility score.

K101Q is a minimally polymorphic accessory mutation weakly selected in patients receiving NVP and EFV (33). It appears to have minimal, if any, detectable effect on NNRTI susceptibility (10). K101R is a polymorphic mutation that is not selected by NNRTIs (3). It has no effect on NNRTI susceptibility (10). K101N/A/T are nonpolymorphic NNRTI-selected mutations (33,14). Their effects on NNRTI susceptibility have not been studied.

K103N/S/H/T/R/Q/E

K103N is a nonpolymorphic mutation selected in patients receiving NVP and EFV (15,34,35,16). It reduces NVP and EFV susceptibility by about 50 and 20-fold, respectively (12,36,37,13,10).

K103S is a nonpolymorphic two base-pair mutation selected by NVP and EFV. It usually occurs in samples from patients who previously had K103N (3,16). It causes intermediate to high-level resistance to these NNRTIs (38,13,10). Because K103S is a 2-bp change from the wildtype K, patients with K103S may be more likely to also 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 (38). K103T is a rare nonpolymorphic mutation that reduces NVP susceptibility by about 10-fold but which has little if any effect on EFV susceptibility (38,39,14).

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 (29). 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 (40,41,16). It causes about a 50-fold reduction in NVP susceptibility and about a 5-fold reduction in EFV susceptibility (42,43,31,44,14,10). Together, V106A and F227L cause high-level resistance to both NVP and EFV (10).

V106M is a nonpolymorphic mutation selected primarily by EFV and NVP. It is particularly common in subtype C viruses (45,46,47,48,49,50,51). It causes >30-fold reduced susceptibility to NVP and EFV (14,10).

V106I is a polymorphic accessory NNRTI-selected mutation (3). Alone it appears to have little, if any effect on NNRTI susceptibility or the virological response to an NNRTI-containing regimen (8,7). In combination with V179D, it may cause low-level resistance to NVP, EFV, ETR, and RPV (52). It has a weight of 1.5 in the Tibotec ETR genotypic susceptibility score (53).

V108I

V108I is a relatively nonpolymorphic accessory mutation that is selected in vitro by NVP (54) and EFV (19) and in patients receiving NVP (16,41), EFV (16,37) and ETR (27). It reduces NVP and EFV susceptibility by about 2-fold (55,12) but does not appear to reduce susceptibility to ETR or RPV (10,8,7).

I132M/L

I132M is an extremely rare nonpolymorphic mutation that reduces NVP and EFV susceptibility in biochemical assays (56,57). It has not been shown to be selected by any of the NNRTIs. I132L is a more common, nonpolymorphic NNRTI-selected mutation that has not been well studied (33).

E138K/A/G/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 up to 5-fold (4,58,59). 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 (60,61,10).

E138A is a polymorphic mutation, which depending on subtype occurs in 0.5% to 5% of viruses from ARV-naive patients (62,63). E138A is weakly selected by ETR and RPV. It reduces ETR (60,64) and RPV (59) susceptibility about 2-fold. It has a weight of 1.5 in the Tibotec ETR genotypic susceptibility score (5). According to the RPV package insert (53), the presence of E138A prior to therapy may reduce the antiviral activity of RPV. In virologically suppressed patients undergoing simplification with TDF/FTC/RPV, the presence of E138A in PBMC DNA at baseline in four patients did not lead to virological rebound (65).

E138Q/G are nonpolymorphic accessory mutations frequently selected by ETR (27,60) and/or RPV (4) and occasionally by NVP and EFV (3). These mutations are associated with 2 to 3-fold reduced susceptibility to ETR and RPV (60,64,10). 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). In one study of subtype C site-directed mutants, these E138Q/G/R were associated with 5-10-fold reduced ETR and RPV susceptibility, E138Q/R were associated with ~10-fold reduced NVP susceptibility, and E138G was associated with ~2-fold reduced NVP and EFV susceptibility (11).

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 and it reduces ETR and RPV susceptibility by 2 to 3-fold (31,10). 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 (3,31,14,64). 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 (64,10,2,5,14). It has a weight of 1.0 in the Tibotec ETR genotypic susceptibility score. The presence of V179D, V179E, or V179T do not appear to interfere with the response to a first-line EFV containing regimen (9,66).

The combination of V179D and K103R act synergistically, reducing NVP and EFV susceptibility >10-fold (29). The combination of V179D and V106I also appear to act synergistically to reduce NVP and EFV susceptibility (52).

V179F is a nonpolymorphic accessory mutation that usually emerges in combination with Y181C. It is one of the most common mutations emerging in NNRTI-experienced patients receiving ETR (27,18). 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) (2,5,14).

V179I is a polymorphic mutation that is frequently selected in patients receiving ETR and RPV (27,18,4). However, it has little, if any, effect on NNRTI susceptibility (8). V179L is a rare nonpolymorphic mutation that is infrequently selected in patients NVP, EFV, and RPV (3,53). Its effect on NNRTI susceptibility is not well studied (64). It is listed as an RPV-associated drug-resistance mutation in the RPV package insert (53).

Y181C/I/V

Y181C is a nonpolymorphic mutation selected in vitro by NVP (67,54), EFV (19), ETR (21), and RPV (2). It is selected in vivo primarily by NVP (16), ETR (27), and RPV (4). It causes >50-fold reduced susceptibility to NVP (12,68,5), about 5-fold reduced susceptibility to ETR (5,31,69), about 3-fold reduced susceptibility to RPV (4), and about 2-fold reduced susceptibility to EFV (12). Although Y181C alone reduces EFV susceptibility by only 2-fold, it has been associated with a reduced response to EFV in patients with virological failure on an NVP-containing regimen. Y181C has a weight of 2.5 in the Tibotec ETR genotypic susceptibility score (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 and RPV (2,53). Y181I/V each have a weight of 3.0 in the Tibotec ETR genotypic susceptibility score (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. Y181S appears to reduce NVP susceptibility about 30-fold (36).

Y188L/C/H

Y188L is a nonpolymorphic 2-base pair mutation selected by NVP and EFV (16,15). It confers high-level resistance (>50-fold reduction in susceptibility) to NVP and EFV (37,12,55,70,13). It is also associated with about 5-fold reduced susceptibility to RPV (71,72,10) and minimally reduced susceptibility to ETR (73,14,11).

Y188C is an uncommon nonpolymorphic mutation selected by NVP and EFV. It confers high-level resistance to NVP (>50-fold reduced susceptibility) and EFV (~20-fold reduced susceptibility) (10). 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 (13,10). It has not been shown to be selected by or to reduce 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

G190A is a nonpolymorphic mutation selected by NVP and EFV (16,15,34). Alone G190A reduces NVP susceptibility >50-fold and EFV susceptibility 5 to 10-fold (12,74,13). It has a weight of 1.0 in the Tibotec ETR genotypic susceptibility score (5) but does not appear to be selected by ETR and RPV or to reduce their susceptibility in the absence of other NNRTI-resistance mutations (14,3,64,10).

G190S is a nonpolymorphic mutation selected by NVP and EFV. G190S causes >50-fold decreased susceptibility to NVP and EFV (12,74,13). It has a weight of 1.5 in the Tibotec ETR genotypic susceptibility score (5) but does not appear to be selected by ETR or RPV or to reduce their susceptibility in the absence of other NNRTI-resistance mutations (14,3,64,10). G190S is the most commonly occurring NNRTI-resistance mutation in subtype A viruses from the countries of the former Soviet Union (A-FSU) because the wildtype glycine in this lineage GGC requires just a single G-to-A mutation for G190S to develop (75). In contrast, this mutation requires a 2-base-pair mutation in nearly all other virus strains.

G190E/Q are uncommon nonpolymorphic mutations selected in patients receiving EFV (3,16,15,76) and in vitro by ETR and RPV (2,1). G190E causes high-level resistance to NVP, EFV, ETR, and RPV (21,2,64,14,10). G190E has been reported to create an HIV-1 PR cleavage site, possibly explaining its poor fitness in cell culture and relative rarity despite its profound effect on NNRTI susceptibility (77). G190Q causes high-level resistance to NVP and EFV (74,10) and likely also reduces ETR and RPV susceptibility.

G190C/T/V are extremely rare nonpolymorphic NNRTI-selected mutations that confer high-level resistance to NVP and EFV (74). 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 (32,16,4,53). Alone it has minimal effects on NNRTI susceptibility (10).

P225H

P225H is a nonpolymorphic accessory mutation selected by EFV that usually occurs in combination with K103N (15,3,76,78). In combination, K103N and P225H reduce NVP and EFV susceptibility >50-fold (12,37).

F227L/C

F227L is a nonpolymorphic mutation selected by NVP and EFV that usually occurs in combination with V106A (16,42). The combination of V106A and F227L confers high-level resistance to NVP and EFV (13,10).

F227C is a rare mutation selected in vitro by ETR and RPV and in patients receiving RPV (4,79). It causes high-level resistance (>10-fold reduced susceptibility) to each of the NNRTIs when present in combination with other NNRTI-resistance mutations (73,39,10). In site-directed mutants, it has been associated with 4- to 5-fold reduced susceptibility to EFV, ETR, and RPV, and 17-fold reduced susceptibility to NVP (11).

M230L/I

M230L is an uncommon nonpolymorphic mutation selected in patients receiving EFV, NVP and RPV (32,6) and by ETR in vitro (21,2). M230L confers intermediate to high-level resistance to each of the NNRTIs (80,21,2,81,10).

M230I is an extremely rare mutation selected in vitro by RPV (2). In a study of site-directed mutants in a subtype C backbone, M230I produced 9, 6, 11, and 16-fold reduced susceptibility to ETR, RPV, EFV, and NVP (11). M230I is also commonly observed in sequences with G-to-A hypermutation and in this setting it should be considered a result of lethal APOBEC-mediated virus editing rather than an indicator of drug resistance (33).

Y232H

Y232H is a rare nonpolymorphic NNRTI-associated TSM that nearly always occurs in combination with other NNRTI-resistance mutations. It is associated with reduced NVP and EFV susceptibility (82,83).

L234I

L234I is an uncommon nonpolymorphic accessory mutation selected in patients receiving NVP and EFV (3). It is also select in vitro by ETR (21) and the investigational NNRTI doravirine (79). 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 (84,85). 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 (3,16). It often occurs in combination with K103N (16). It reduces susceptibility to NVP and EFV by about 5-fold (29,3) and possibly reduces susceptibility to ETR and RPV (14,64). 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 (32,14,64).

Y318F

Y318F is a nonpolymorphic mutation occasionally selected in patients receiving NVP and EFV (16). It has also been selected in vitro by ETR (21). It reduces NVP susceptibility by about 5-fold but has little phenotypic effect on the remaining NNRTIs (86,21).

N348I

N348I is a nonpolymorphic accessory mutation selected by NVP and EFV and the NRTIs AZT and d4T (87,88,89). Alone it reduces AZT susceptibility about 3-fold and NVP and EFV susceptibility by 3-fold and 2-fold, respectively (87,88,23,69). It has been proposed that N348I may reduce RNaseH cleavage thereby allowing more time for NNRTI dissociation and re-initiation of DNA synthesis (90,91).

References

  1. 1.0 1.1 1.2 Asahchop EL, Oliveira M, Wainberg MA, Brenner BG, Moisi D, Toni, Td and Tremblay CL. Characterization of the E138K resistance mutation in HIV-1 reverse transcriptase conferring susceptibility to etravirine in B and non-B HIV-1 subtypes. Antimicrob Agents Chemother 2011.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 2.14 Azijn H, Tirry I, Vingerhoets J, de Bethune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G and Rimsky LT. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother 2010.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 Rhee SY, Gonzales MJ, Kantor R, Betts BJ, Ravela J and Shafer RW. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 2003.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 4.12 4.13 Rimsky L, Vingerhoets J, Van Eygen V, Eron J, Clotet B, Hoogstoel A, Boven K and Picchio G. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis. J Acquir Immune Defic Syndr 2012.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 Vingerhoets J, Tambuyzer L, Azijn H, Hoogstoel A, Nijs S, Peeters M, de Bethune MP, De Smedt G, Woodfall B and Picchio G. Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies. AIDS 2010.
  6. 6.0 6.1 Rimsky L, Van Eygen V, Hoogstoel A, Stevens M, Boven K, Picchio G and Vingerhoets J. 96-Week resistance analyses of rilpivirine in treatment-naive, HIV-1-infected adults from the ECHO and THRIVE Phase III trials. Antivir Ther 2013.
  7. 7.0 7.1 7.2 Geretti AM, Conibear T, Hill A, Johnson JA, Tambuyzer L, Thys K, Vingerhoets J, Van Delft Y and Group, Sense Study. Sensitive testing of plasma HIV-1 RNA and Sanger sequencing of cellular HIV-1 DNA for the detection of drug resistance prior to starting first-line antiretroviral therapy with etravirine or efavirenz. J Antimicrob Chemother 2014.
  8. 8.0 8.1 8.2 8.3 Vingerhoets J, Rimsky L, Van Eygen V, Nijs S, Vanveggel S, Boven K and Picchio G. Pre-existing mutations in the rilpivirine Phase III trials ECHO and THRIVE: prevalence and impact on virological response. Antivir Ther 2013.
  9. 9.0 9.1 Mackie NE, Dunn DT, Dolling D, Garvey L, Harrison L, Fearnhill E, Tilston P, Sabin C, Geretti AM, Database, Uk Hiv Drug Resistance and study, Uk Chic. The impact of HIV-1 reverse transcriptase polymorphisms on responses to first-line nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-1-infected adults. AIDS 2013.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17 10.18 10.19 10.20 10.21 10.22 10.23 10.24 10.25 10.26 10.27 10.28 Melikian GL, Rhee SY, Varghese V, Porter D, White K, Taylor J, Towner W, Troia P, Burack J, Dejesus E, Robbins GK, Razzeca K, Kagan R, Liu TF, Fessel WJ, Israelski D and Shafer RW. Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing. J Antimicrob Chemother 2014.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 Basson AE, Rhee SY, Parry CM, El-Khatib Z, Charalambous S, De Oliveira T, Pillay D, Hoffmann C, Katzenstein D, Shafer RW and Morris L. Impact of drug resistance-associated amino acid changes in HIV-1 subtype C on susceptibility to newer nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2015.
  12. 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 12.9 Rhee SY, Liu T, Ravela J, Gonzales MJ and Shafer RW. Distribution of human immunodeficiency virus type 1 protease and reverse transcriptase mutation patterns in 4,183 persons undergoing genotypic resistance testing. Antimicrob Agents Chemother 2004.
  13. 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 Zhang Z, Xu W, Koh YH, Shim JH, Girardet JL, Yeh LT, Hamatake RK and Hong Z. A novel nonnucleoside analogue that inhibits human immunodeficiency virus type 1 isolates resistant to current nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2007.
  14. 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 14.9 14.10 14.11 14.12 14.13 14.14 van Westen GJ, Hendriks A, Wegner JK, Ijzerman AP, van Vlijmen HW and Bender A. Significantly Improved HIV Inhibitor Efficacy Prediction Employing Proteochemometric Models Generated From Antivirogram Data. PLoS Comput Biol 2013.
  15. 15.0 15.1 15.2 15.3 15.4 15.5 15.6 15.7 Bacheler LT, Anton ED, Kudish P, Baker D, Bunville J, Krakowski K, Bolling L, Aujay M, Wang XV, Ellis D, Becker MF, Lasut AL, George HJ, Spalding DR, Hollis G and Abremski K. Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy. Antimicrob Agents Chemother 2000.
  16. 16.0 16.1 16.2 16.3 16.4 16.5 16.6 16.7 16.8 16.9 16.10 16.11 16.12 16.13 16.14 16.15 16.16 16.17 Reuman EC, Rhee SY, Holmes SP and Shafer RW. Constrained patterns of covariation and clustering of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations. J Antimicrob Chemother 2010.
  17. ^  and Croxtall JD. Etravirine: a review of its use in the management of treatment-experienced patients with HIV-1 infection. Drugs 2012.
  18. 18.0 18.1 18.2 Marcelin AG, Descamps D, Tamalet C, Cottalorda J, Izopet J, Delaugerre C, Morand-Joubert L, Trabaud MA, Bettinger D, Rogez S, Ruffault A, Henquell C, Signori-Schmuck A, Bouvier-Alias M, Vallet S, Masquelier B, Flandre P and Calvez V. Emerging mutations and associated factors in patients displaying treatment failure on an etravirine-containing regimen. Antivir Ther 2012.
  19. 19.0 19.1 19.2 Winslow DL, Garber S, Reid C, Scarnati H, Baker D, Rayner MM and Anton ED. Selection conditions affect the evolution of specific mutations in the reverse transcriptase gene associated with resistance to DMP 266. AIDS 1996.
  20. ^ Corbau R, Mori J, Phillips C, Fishburn L, Martin A, Mowbray C, Panton W, Smith-Burchnell C, Thornberry A, Ringrose H, Knochel T, Irving S, Westby M, Wood A and Perros M. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2010.
  21. 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L, Jochmans D, Andries K, Pauwels R and de Bethune MP. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 2005.
  22. ^ Asahchop EL, Wainberg MA, Oliveira M, Xu H, Brenner BG, Moisi D, Ibanescu IR and Tremblay C. Distinct resistance patterns to etravirine and rilpivirine in viruses containing nnrti mutations at baseline. AIDS 2012.
  23. 23.0 23.1 23.2 Gupta S, Fransen S, Paxinos EE, Stawiski E, Huang W and Petropoulos CJ. Combinations of mutations in the connection domain of human immunodeficiency virus type 1 reverse transcriptase: assessing the impact on nucleoside and nonnucleoside reverse transcriptase inhibitor resistance. Antimicrob Agents Chemother 2010.
  24. ^ Haddad M Napolitano LA Frantzell A, Vingerhoets J, Rimsky L, de Meyer S, Paquet A, Petropoulos C, Whitcomb, J and Huang W. Combinations of HIV-1 reverse transcriptase mutations L100I + K103N/S and L100I + K103R + V179D reduce susceptibility to rilpivirine.. Conference on Retroviruses and Opportunistic Infections 2013.
  25. 25.0 25.1 Balamane M, Varghese V, Melikian GL, Fessel WJ, Katzenstein DA and Shafer RW. Panel of prototypical recombinant infectious molecular clones resistant to nevirapine, efavirenz, etravirine, and rilpivirine. Antimicrob Agents Chemother 2012.
  26. ^ Van der Borght K, Verheyen A, Feyaerts M, Van Wesenbeeck L, Verlinden Y, Van Craenenbroeck E and van Vlijmen H. Quantitative prediction of integrase inhibitor resistance from genotype through consensus linear regression modeling. Virol J 2013.
  27. 27.0 27.1 27.2 27.3 27.4 27.5 27.6 27.7 27.8 27.9 Tambuyzer L, Vingerhoets J, Azijn H, Daems B, Nijs S, de Bethune MP and Picchio G. Characterization of genotypic and phenotypic changes in HIV-1-infected patients with virologic failure on an etravirine-containing regimen in the DUET-1 and DUET-2 clinical studies. AIDS Res Hum Retroviruses 2010.
  28. ^ Pingen M, van der Ende ME, Wensing AM, el Barzouhi A, Simen BB, Schutten M and Boucher CA. Deep sequencing does not reveal additional transmitted mutations in patients diagnosed with HIV-1 variants with single nucleoside reverse transcriptase inhibitor resistance mutations. HIV Med 2013.
  29. 29.0 29.1 29.2 29.3 Parkin NT, Gupta S, Chappey C and Petropoulos CJ. The K101P and K103R/V179D Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Resistance to Nonnucleoside Reverse Transcriptase Inhibitors. Antimicrob Agents Chemother 2006.
  30. ^ Kagan RM, Sista P, Pattery T, Bacheler L and Schwab DA. Additional HIV-1 mutation patterns associated with reduced phenotypic susceptibility to etravirine in clinical samples. AIDS 2009.
  31. 31.0 31.1 31.2 31.3 31.4 Tambuyzer L, Azijn H, Rimsky LT, Vingerhoets J, Lecocq P, Kraus G, Picchio G and de Bethune MP. Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors. Antivir Ther 2009.
  32. 32.0 32.1 32.2 32.3 Shahriar R, Rhee SY, Liu TF, Fessel WJ, Scarsella A, Towner W, Holmes SP, Zolopa AR and Shafer RW. Nonpolymorphic human immunodeficiency virus type 1 protease and reverse transcriptase treatment-selected mutations. Antimicrob Agents Chemother 2009.
  33. 33.0 33.1 33.2 33.3 Rhee SY, Sankaran K, Varghese V, Winters M, Hurt CB, Eron JJ, Parkin N, Holmes SP, Holodniy M and Shafer RW. HIV-1 Protease, Reverse Transcriptase, and Integrase Variation. J Virol 2016.
  34. 34.0 34.1 Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA, 3rd Acosta EP, Schackman BR, Pilcher CD, Murphy RL, Maher WE, Witt MD, Reichman RC, Snyder S, Klingman KL and Kuritzkes DR. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004.
  35. ^ Margot NA, Lu B, Cheng A and Miller MD. Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903. HIV Med 2006.
  36. 36.0 36.1 Eshleman SH, Jones D, Galovich J, Paxinos EE, Petropoulos CJ, Jackson JB and Parkin N. Phenotypic drug resistance patterns in subtype A HIV-1 clones with nonnucleoside reverse transcriptase resistance mutations. AIDS Res Hum Retroviruses 2006.
  37. 37.0 37.1 37.2 37.3 Bacheler L, Jeffrey S, Hanna G, D'Aquila R, Wallace L, Logue K, Cordova B, Hertogs K, Larder B, Buckery R, Baker D, Gallagher K, Scarnati H, Tritch R and Rizzo C. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J Virol 2001.
  38. 38.0 38.1 38.2 Harrigan PR, Mo T, Wynhoven B, Hirsch J, Brumme Z, McKenna P, Pattery T, Vingerhoets J and Bacheler LT. Rare mutations at codon 103 of HIV-1 reverse transcriptase can confer resistance to non-nucleoside reverse transcriptase inhibitors. AIDS 2005.
  39. 39.0 39.1 Sato A, Hammond J, Alexander TN, Graham JP, Binford S, Sugita K, Sugimoto H, Fujiwara T and Patick AK. In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor. Antiviral Res 2006.
  40. ^ Larder BA, Kellam P and Kemp SD. Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. Nature 1993.
  41. 41.0 41.1 Richman DD, Havlir D, Corbeil J, Looney D, Ignacio C, Spector SA, Sullivan J, Cheeseman S, Barringer K, Pauletti D and et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994.
  42. 42.0 42.1 Balzarini J, Pelemans H, Esnouf R and De Clercq E. A novel mutation (F227L) arises in the reverse transcriptase of human immunodeficiency virus type 1 on dose-escalating treatment of HIV type 1-infected cell cultures with the nonnucleoside reverse transcriptase inhibitor thiocarboxanilide UC-781. AIDS Res Hum Retroviruses 1998.
  43. ^ Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W, Tian H, Smith D, Winslow GA, Capon DJ and Whitcomb JM. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 2000.
  44. ^ Parkin NT, Hellmann NS, Whitcomb JM, Kiss L, Chappey C and Petropoulos CJ. Natural variation of drug susceptibility in wild-type human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004.
  45. ^ Brenner B, Turner D, Oliveira M, Moisi D, Detorio M, Carobene M, Marlink RG, Schapiro J, Roger M and Wainberg MA. A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS 2003.
  46. ^ Grossman Z, Istomin V, Averbuch D, Lorber M, Risenberg K, Levi I, Chowers M, Burke M, Bar Yaacov N and Schapiro JM. Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C. AIDS 2004.
  47. ^ Wallis CL, Mellors JW, Venter WD, Sanne I and Stevens W. Varied patterns of HIV-1 drug resistance on failing first-line antiretroviral therapy in South Africa. J Acquir Immune Defic Syndr 2010.
  48. ^ El-Khatib Z, Ekstrom AM, Ledwaba J, Mohapi L, Laher F, Karstaedt A, Charalambous S, Petzold M, Katzenstein D and Morris L. Viremia and drug resistance among HIV-1 patients on antiretroviral treatment: a cross-sectional study in Soweto, South Africa. AIDS 2010.
  49. ^ Green TN, Archary M, Gordon ML, Padayachi N, Lie Y, Anton ED, Reeves JD, Grobler A, Bobat R, Coovadia H and Ndung'u T. Drug resistance and coreceptor usage in HIV type 1 subtype C-infected children initiating or failing highly active antiretroviral therapy in South Africa. AIDS Res Hum Retroviruses 2012.
  50. ^ van Zyl GU, van der Merwe L, Claassen M, Zeier M and Preiser W. Antiretroviral resistance patterns and factors associated with resistance in adult patients failing NNRTI-based regimens in the Western Cape, South Africa. J Med Virol 2011.
  51. ^ Marconi VC, Sunpath H, Lu Z, Gordon M, Koranteng-Apeagyei K, Hampton J, Carpenter S, Giddy J, Ross D, Holst H, Losina E, Walker BD and Kuritzkes DR. Prevalence of HIV-1 drug resistance after failure of a first highly active antiretroviral therapy regimen in KwaZulu Natal, South Africa. Clin Infect Dis 2008.
  52. 52.0 52.1 Gatanaga H, Ode H, Hachiya A, Hayashida T, Sato H and Oka S. Combination of V106I and V179D polymorphic mutations in human immunodeficiency virus type 1 reverse transcriptase confers resistance to efavirenz and nevirapine but not etravirine. Antimicrob Agents Chemother 2010.
  53. 53.0 53.1 53.2 53.3 53.4 53.5  and FDA. Edurant (Rilpivirine): Highlights of prescribing information. http://www.edurant.com/shared/product/Edurant/EDURANT-PI.pdf 2012.
  54. 54.0 54.1 Wu H, Zhang HJ, Zhang XM, Xu HF, Wang M, Huang JD and Zheng BJ. Identification of drug resistant mutations in HIV-1 CRF07_BC variants selected by nevirapine in vitro. PLoS One 2012.
  55. 55.0 55.1 Vermeiren H, Van Craenenbroeck E, Alen P, Bacheler L, Picchio G and Lecocq P. Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling. J Virol Methods 2007.
  56. ^ Ambrose Z, Herman BD, Sheen CW, Zelina S, Moore KL, Tachedjian G, Nissley DV and Sluis-Cremer N. The human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor resistance mutation I132M confers hypersensitivity to nucleoside analogs. J Virol 2009.
  57. ^ Nissley DV, Radzio J, Ambrose Z, Sheen CW, Hamamouch N, Moore KL, Tachedjian G and Sluis-Cremer N. Characterization of novel non-nucleoside reverse transcriptase (RT) inhibitor resistance mutations at residues 132 and 135 in the 51 kDa subunit of HIV-1 RT. Biochem J 2007.
  58. ^ Kulkarni R, Babaoglu K, Lansdon EB, Rimsky L, Van Eygen V, Picchio G, Svarovskaia E, Miller MD and White KL. The HIV-1 reverse transcriptase M184I mutation enhances the E138K-associated resistance to rilpivirine and decreases viral fitness. J Acquir Immune Defic Syndr 2012.
  59. 59.0 59.1 Haddad M, Napolitano LA Paquet AC Evans MD Petropoulos CJ, Whitcomb J Rimsky L, Vingerhoets J, Picchio G and Coakley E. Impact of HIV-1 reverse transcriptase E138 mutations on rilpivirine drug susceptibility [abstract 10]. Antivir Ther 2011.
  60. 60.0 60.1 60.2 60.3 Tambuyzer L, Nijs S, Daems B, Picchio G and Vingerhoets J. Effect of mutations at position E138 in HIV-1 reverse transcriptase on phenotypic susceptibility and virologic response to etravirine. J Acquir Immune Defic Syndr 2011.
  61. ^ Xu HT, Colby-Germinario SP, Huang W, Oliveira M, Han Y, Quan Y, Petropoulos CJ and Wainberg MA. Role of the K101E substitution in HIV-1 reverse transcriptase in resistance to rilpivirine and other nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2013.
  62. ^ Sluis-Cremer N, Jordan MR, Huber K, Wallis CL, Bertagnolio S, Mellors JW, Parkin NT and Harrigan PR. E138A in HIV-1 reverse transcriptase is more common in subtype C than B: implications for rilpivirine use in resource-limited settings. Antiviral Res 2014.
  63. ^ Theys K, Van Laethem K, Gomes P, Baele G, Pineda-Pena AC, Vandamme AM, Camacho RJ and Abecasis AB. Sub-Epidemics Explain Localized High Prevalence of Reduced Susceptibility to Rilpivirine in Treatment-Naive HIV-1-Infected Patients: Subtype and Geographic Compartmentalization of Baseline Resistance Mutations. AIDS Res Hum Retroviruses 2016.
  64. 64.0 64.1 64.2 64.3 64.4 64.5 64.6 64.7 64.8 64.9 Haddad, M, Stawiski, E, Benhamida, J and Coakley E. Improved genotypic algorithm for predicting etravirine susceptibility: Comprehensive list of mutations identified through correlation with matched phenotype. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy 2010.
  65. ^ Porter DP, Toma J, Tan Y, Solberg O, Cai S, Kulkarni R, Andreatta K, Lie Y, Chuck SK, Palella F, Miller MD and White KL. Clinical Outcomes of Virologically-Suppressed Patients with Pre-existing HIV-1 Drug Resistance Mutations Switching to Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in the SPIRIT Study. HIV Clin Trials 2016.
  66. ^ Lim C, McFaul K, Kabagambe S, Sonecha S, Jones R, Asboe D, Pozniak A, Nwokolo N and Boffito M. Comparison of efavirenz- and protease inhibitor-based cART regimens in treatmentnaive PLWH with baseline resistance. AIDS 2016.
  67. ^ Richman D, Shih CK, Lowy I, Rose J, Prodanovich P, Goff S and Griffin J. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci U S A 1991.
  68. ^ Eshleman SH, Guay LA, Mwatha A, Brown ER, Cunningham SP, Musoke P, Mmiro F and Jackson JB. Characterization of nevirapine resistance mutations in women with subtype A vs. D HIV-1 6-8 weeks after single-dose nevirapine (HIVNET 012). J Acquir Immune Defic Syndr 2004.
  69. 69.0 69.1 Gupta S, Vingerhoets J, Fransen S, Tambuyzer L, Azijn H, Frantzell A, Paredes R, Coakley E, Nijs S, Clotet B, Petropoulos CJ, Schapiro J, Huang W and Picchio G. Connection domain mutations in HIV-1 reverse transcriptase do not impact etravirine susceptibility and virologic responses to etravirine-containing regimens. Antimicrob Agents Chemother 2011.
  70. ^ Baxter JD, Schapiro JM, Boucher CA, Kohlbrenner VM, Hall DB, Scherer JR and Mayers DL. Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir. J Virol 2006.
  71. ^ Haddad M Napolitano LA Paquet AC Evans MD Petropoulos CJ, Whitcomb, J and Huang W. Mutation Y188L of HIV-1 reverse transciptase is strongly associated with reduced susceptibility to rilpivirine. Conference on Retroviruses and Opportunistic Infections 2012.
  72. ^ Johnson BC, Pauly GT, Rai G, Patel D, Bauman JD, Baker HL, Das K, Schneider JP, Maloney DJ, Arnold E, Thomas CJ and Hughes SH. A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants. Retrovirology 2012.
  73. 73.0 73.1 Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, Janssen P, De Corte B, Vingerhoets J, Pauwels R and de Bethune MP. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004.
  74. 74.0 74.1 74.2 74.3 Huang W, Gamarnik A, Limoli K, Petropoulos CJ and Whitcomb JM. Amino acid substitutions at position 190 of human immunodeficiency virus type 1 reverse transcriptase increase susceptibility to delavirdine and impair virus replication. J Virol 2003.
  75. ^ Kolomeets AN, Varghese V, Lemey P, Bobkova MR and Shafer RW. A uniquely prevalent nonnucleoside reverse transcriptase inhibitor resistance mutation in Russian subtype A HIV-1 viruses. AIDS 2014.
  76. 76.0 76.1 Alcaro S, Alteri C, Artese A, Ceccherini-Silberstein F, Costa G, Ortuso F, Bertoli A, Forbici F, Santoro MM, Parrotta L, Flandre P, Masquelier B, Descamps D, Calvez V, Marcelin AG, Perno CF, Sing T and Svicher V. Docking analysis and resistance evaluation of clinically relevant mutations associated with the HIV-1 non-nucleoside reverse transcriptase inhibitors nevirapine, efavirenz and etravirine. ChemMedChem 2011.
  77. ^ Dunn LL, Boyer PL, McWilliams MJ, Smith SJ and Hughes SH. Mutations in human immunodeficiency virus type 1 reverse transcriptase that make it sensitive to degradation by the viral protease in virions are selected against in patients. Virology 2015.
  78. ^ Koval CE, Dykes C, Wang J and Demeter LM. Relative replication fitness of efavirenz-resistant mutants of HIV-1: correlation with frequency during clinical therapy and evidence of compensation for the reduced fitness of K103N + L100I by the nucleoside resistance mutation L74V. Virology 2006.
  79. 79.0 79.1 Feng M, Wang D, Grobler JA, Hazuda DJ, Miller MD and Lai MT. In vitro resistance selection with doravirine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with distinct mutation development pathways. Antimicrob Agents Chemother 2015.
  80. ^ Huang W, Parkin NT, Lie YS, Wrin T, Haubrich R, Deeks S, Hellmann N, Petropoulos CJ and Whitcomb JM. A novel HIV-1 RT mutation (M230L) confers NNRTI resistance and dose-dependent stimulation of replication. Antivir Ther 2000.
  81. ^ Xu HT, Quan Y, Schader SM, Oliveira M, Bar-Magen T and Wainberg MA. The M230L nonnucleoside reverse transcriptase inhibitor resistance mutation in HIV-1 reverse transcriptase impairs enzymatic function and viral replicative capacity. Antimicrob Agents Chemother 2010.
  82. ^ Wu H, Zhang XM, Zhang HJ, Zhang Q, Chen Z, Huang JD, Lee SS and Zheng BJ. In vitro selection of HIV-1 CRF08_BC variants resistant to reverse transcriptase inhibitors. AIDS Res Hum Retroviruses 2015.
  83. ^ Zhang XM, Zhang Q, Wu H, Lau TC, Liu X, Chu H, Zhang K, Zhou J, Chen Z, Jin DY and Zheng BJ. Novel mutations L228I and Y232H cause NNRTI resistance in combinational pattern. AIDS Res Hum Retroviruses 2016.
  84. ^ Dueweke TJ, Pushkarskaya T, Poppe SM, Swaney SM, Zhao JQ, Chen IS, Stevenson M and Tarpley WG. A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proc Natl Acad Sci U S A 1993.
  85. ^ Demeter LM, Shafer RW, Meehan PM, Holden-Wiltse J, Fischl MA, Freimuth WW, Para MF and Reichman RC. Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260). Antimicrob Agents Chemother 2000.
  86. ^ Harrigan PR, Salim M, Stammers DK, Wynhoven B, Brumme ZL, McKenna P, Larder B and Kemp SD. A Mutation in the 3' region of the human immunodeficiency virus type 1 reverse transcriptase (Y318F) associated with nonnucleoside reverse transcriptase inhibitor resistance. J Virol 2002.
  87. 87.0 87.1 Yap SH, Sheen CW, Fahey J, Zanin M, Tyssen D, Lima VD, Wynhoven B, Kuiper M, Sluis-Cremer N, Harrigan PR and Tachedjian G. N348I in the Connection Domain of HIV-1 Reverse Transcriptase Confers Zidovudine and Nevirapine Resistance. PLoS Med 2007.
  88. 88.0 88.1 Hachiya A, Kodama EN, Sarafianos SG, Schuckmann MM, Sakagami Y, Matsuoka M, Takiguchi M, Gatanaga H and Oka S. Amino acid mutation N348I in the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase confers multiclass resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. J Virol 2008.
  89. ^ Waters JM, O'Neal W, White KL, Wakeford C, Lansdon EB, Harris J, Svarovskaia ES, Miller MD and Borroto-Esoda K. Mutations in the thumb-connection and RNase H domain of HIV type-1 reverse transcriptase of antiretroviral treatment-experienced patients. Antivir Ther 2009.
  90. ^ Nikolenko GN, Delviks-Frankenberry KA and Pathak VK. A novel molecular mechanism of dual resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. J Virol 2010.
  91. ^ Menendez-Arias L, Betancor G and Matamoros T. HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors. Antiviral Res 2011.