Major Integrase Inhibitor (INSTI) Resistance Mutations
The table lists the most common clinically significant INSTI-resistance mutations. Mutations in bold red are associated with the highest levels of reduced susceptibility or virological response to the indicated INSTI. Mutations in bold reduce INSTI susceptibility or virological response. Mutations in plain text contribute to reduced suceptibility in combination with other INSTI-resistance mutations.
H51Y is a rare nonpolymorphic accessory mutation. It is selected in vitro by EVG (1,2,3) and DTG (4) and in patients receiving RAL (5,6) and EVG (7,8). It reduces EVG susceptibility by ~2-3-fold (1,3,4,9,10) but alone does not appear to reduce RAL, DTG, or BIC susceptibility (3,4,11,12).
T66A is a nonpolymorphic mutation selected in patients receiving EVG (5,13,8,14) and RAL (15,16,5). It reduces EVG susceptibility ~5-fold but has minimal effect on RAL, DTG or BIC susceptibility (17,3,18,19,20,10).
T66I is a nonpolymorphic mutation frequently selected in vitro (2,1,21,3,22) and in patients receiving EVG (2,1,21,7,8). It has also been reported in patients receiving RAL (23) and DTG (24). T66I reduces EVG susceptibility ~10-fold (17,3,25,18,19) but does not reduce RAL (17,25,3,18,20), DTG, (19,26,10), or BIC (12) susceptibility.
T66K is a nonpolymorphic mutation selected in vitro by EVG (3). It has also been selected in patients receiving EVG (13,19) and RAL (23). It is associated with >40-fold reduced EVG susceptibility (17,3,19), >10-fold reduced RAL susceptibility (17,3,19,10) and 2-3-fold reduced DTG susceptibility (17,19,10).
L74M occurs in nearly 10% of CRF02_AG viruses from ARV-naïve patients but is otherwise minimally polymorphic with an ARV-naive prevalence ranging between 0.3% to 3% in other subtypes (27). It is selected in patients receiving RAL (28,29,30,31,23) and EVG (5,8), and in RAL-experienced patients receiving DTG salvage therapy (32,33). By itself, it has minimal if any effect on INSTI susceptibility (25,34,10). However, it reduces RAL susceptibility in combination with other INSTI-resistance mutations (22,25,6). In combination with mutations at positions 140 and 148, it reduces DTG susceptibility (17) and the clinical response to DTG-salvage therapy regimens (32,32).
L74I is highly polymorphic, occurring in 3% to 30% of viruses from ARV-naïve patients depending on subtype (27). It may be weakly selected by INSTI therapy. It does not appear to be associated with reduced INSTI susceptibility.
L74F is an extremely rare mutation reported in one RAL-treated patient (35). Alone, it minimally reduces RAL and EVG susceptibility. In combination with G140S and Q148H it contributes to reduced DTG susceptibility (35).
E92Q is a nonpolymorphic mutation selected in patients receiving RAL (28,5,7,8) and EVG (5,13,36,7). It reduces RAL susceptibility ~5-fold (17,25,18,19) and EVG susceptibility ~30-fold (1,17,25,18,19). It is often the primary mutation associated with VF on an EVG-containing regimen (7,8). It is selected in vitro by DTG and reduces DTG susceptibility ~1.5-fold (17,19,37,38). It does not appear to reduce BIC susceptibility (39).
E92G is a nonpolymorphic mutation selected in vitro by EVG (3) and in patients receiving RAL and EVG (8,19). It reduces EVG susceptibility ~10-fold (3,19) but does not reduce RAL, or DTG susceptibility (3,19).
E92V has been reported to emerge during in vitro passage with an investigational INSTI and to reduce EVG and possibly RAL but not DTG susceptibility (25,17). It has rarely been reported in patients receiving INSTIs (23).
T97A is a polymorphic accessory INSTI-resistance mutation occurring in 1% to 4% of viruses from untreated persons depending on subtype (27). (40,41)(Kolomeets et al., 2014; ) It is selected in patients receiving RAL (42,43,6,8), EVG (8), and DTG (32,33). It reduces EVG susceptibility by ~3-fold (10), but has not been shown to reduce the efficacy of first-line EVG-containing regimens (44). Alone, it has minimal if any effect on RAL or DTG susceptibility but it contributes to markedly reduced RAL (32,45) and DTG susceptibility when combined with other INSTI-resistance mutations (33,46).
G118R is a rare nonpolymorphic accessory mutation selected in vitro by DTG (11,47). It has also been selected in one patient receiving RAL (48) and eight patients receiving DTG (47,49,50,51,52). Overall reductions in susceptibility are ~5-10-fold for RAL and EVG, ~5-fold for DTG, and ~2-3-fold for BIC (22,48,9,47,53,11,54,55,12,56). G118R is also commonly observed in sequences with G-to-A hypermutation and in this setting it should not be considered an indicator of drug resistance (57).
F121Y is a nonpolymorphic mutation that is selected in vitro by RAL (58,37) and EVG (1) and rarely in vivo by RAL (59) It reduces susceptibility to RAL and EVG ~5 and >10-fold, respectively (1,22,9,10). It has been shown to have minimal if any effect on DTG susceptibility (60,10,39,17,54,55,39).
E138K/A are nonpolymorphic accessory resistance mutations selected in patients receiving RAL (28,61,57,23), EVG (13), and DTG (32,33) usually in combination with Q148 mutations. Alone they do not reduce INSTI susceptibility (2,25,17,10). In combination with Q148 mutations they reduce RAL and EVG susceptibility >100-fold (45,62,10) and DTG susceptibility up to 10-fold (32,63,17,10). E138T is a less common INSTI-selected nonpolymorphic accessory resistance mutation (57,38,33).
G140S is a nonpolymorphic mutation that usually occurs with Q148H/R/K in patients receiving RAL (28,64,5,30,43,15) and EVG (13,7,8). Alone, it reduces EVG susceptibility 3-5-fold but does not reduce RAL or DTG susceptibility (17,10). In combination with Q148H/R/K, it reduces RAL and EVG susceptibility >100-fold and DTG up to 10-fold (63). G140A/C are less well-studied nonpolymorphic variants that appear to have effects similar to G140S (65,66,67).
P142T is a rare nonpolymorphic mutation selected in vitro (68,37) and in vivo by RAL (33,57). It usually occurs in combination with other INSTI-resistance mutations. Its effect on susceptibility has not been studied.
Y143C/R are nonpolymorphic mutations selected by RAL (64,28,69,43,9,64,70,30). Alone, Y143C and Y143R reduce RAL susceptibility by ~5 and 20-fold respectively (28,9,62,64,30) but with T97A or other accessory mutations, they reduce RAL susceptibility >100-fold (45,64,28,9). Y143H is a less common mutation at this position, which is likely a transitional mutation between the wildtype Y and the 2-base pair mutation R. Alone, Y143C/R mutations have minimal effects on EVG susceptibility (17,19,30,18). However, in combination with multiple additional accessory INSTI-resistance mutations including L74M, T97A, G163R, and S230R they reduce EVG susceptibility up to 10-20 fold (32). Y143 mutations do not reduce DTG or BIC susceptibility (30,20,18,17,39).
S147G is a nonpolymorphic mutation selected in patients receiving EVG (13,8). It reduces EVG susceptibility about 5-fold but has minimal if any effect on RAL, or DTG susceptibility (3,1,18,19,10). It has also been selected in patients receiving DTG monotherapy (73) and DTG salvage therapy (33).
Q148H/K/R are nonpolymorphic mutations selected in patients receiving RAL and EVG, (29,64,8,5,45,43,30,74,31,15). Q148H/R has been reported in patients with VF during DTG mono- (75,50,73) or salvage therapy (33).
By itself, Q148H reduces RAL and EVG susceptibility about 5-10 fold and Q148R/K reduce RAL and EVG susceptibility 30-100 fold (45,17,19,21,34,30,62). With G140S/A, Q148H/R/K reduce RAL and EVG susceptibility >100-fold. (45,17,19,21,34,30,62). By themselves, Q148H/K/R alone have minimal effects on DTG and BIC susceptibility (17,76,19,39,12). However, in combination with E138K ± G140SA, Q148 mutations (and particularly Q148K) reduce DTG and BIC susceptibility up to 10-fold (17,32,76,19,39,67,12). The combination of Q148H/R/K + (E138K ± G140S/A) + one or two additional mutations such as N155H or the accessory mutations L74M and T97A, cause even higher levels of reduced DTG and BIC susceptibility (33,46,67,12).
Q148N is a rare INSTI-selected mutation that causes reduces EVG susceptibility ~3-fold. It may represent a Q148H or Q148K revertant (77).
In subtype B viruses G140 is encoded primarily by GGT or GGC whereas for most other subtypes, G140 is encoded primarily by GGG or GGA. Therefore, a single G to A change at the first position of the G140 codon results in a serine in subtype B viruses. G140S is an important compensatory mutation for Q148 mutations and this may explain why Q148 mutations occur significantly more commonly in subtype B viruses compared to non-B viruses from patients with RAL VF (78,79,80).
G149A selected in vivo by DTG in RAL experienced patients (33) and selected in vitro by CAB (81). It appears to have no effect by itself but in combination with mutations at positions 140 and 148, it reduces DTG and CAB susceptibility (81).
V151I is a polymorphic accessory INSTI-selected mutation occurring in 1% to 6% of viruses depending on subtype (27). It is selected in vitro by EVG (22) and in vivo by RAL (28). It appears to have little or no effect on INSTI susceptibility (82). V151L is an extremely rare nonpolymorphic mutation selected in vitro by early investigational INSTIs but it has not been reported in patients receiving INSTIs. It reduces susceptibility to RAL, EVG, and DTG by 10-15, 20-30, and 2-3-fold, respectively (17,10). V151A is an extremely rare nonpolymorphic mutation that has been selected in vitro by an investigational INSTI and it has been associated with ~3-fold reduced EVG susceptibility (25,10).
S153Y/F are extremely rare nonpolymorphic mutations selected in vitro by EVG (3,1), DTG (17,17), and BIC (67). S153F is also selected in vitro by DTG (17). Each mutation reduces EVG, DTG, and BIC susceptibility ~2-3-fold respectively (17,38,10,67,39).
N155H is a nonpolymorphic mutation selected in patients receiving RAL and EVG (29,64,8,5,45,43,30,74,31,15,13,7,8,66). By itself, it reduces RAL and EVG susceptibility ~10 and 30-fold, respectively (17,3,25,64,18,45). N155H has been selected by DTG in INSTI-naïve (83,84,73) and RAL-experienced patients (32). N155S/T are extremely rare nonpolymorphic mutations that reduce RAL and EVG susceptibility less than N155H (17,25,20,17). N155D is a rare nonpolymorphic INSTI-selected mutation that has not been well-characterized (57).
E157Q occurs in ~2-5% of viruses from ARV-naïve patients depending on subtype (27). It is commonly selected during INSTI therapy (27). It has minimal if any effect on RAL, EVG, or DTG susceptibility () (34,9,87,88,89) and alone it does not appear to influence the response to INSTI therapy (89).
G163RK are nonpolymorphic in all subtypes except subtype F (57). They have been shown to be selected in subtype B patients receiving RAL. They appear to be accessory mutations as they usually occur in combination with other INI-resistance mutations particularly N155H (28,16,29). G163E is a polymorphic mutation that does not appear to be selected by INSTIs.
S230R is a nonpolymorphic mutation selected in vitro and in vivo by RAL and in vitro by EVG (21). It has also been selected in patients receiving an incompletely suppressive DTG-containing regimen (83,84). Alone, it reduces DTG susceptibility ~3-fold but does not appear to reduce RAL or EVG susceptibility (90).
R263K is a nonpolymorphic mutation selected in vitro by EVG (3), DTG (4,91) and BIC (39,67). It occurs in a high proportion of patients developing VF on an incompletely suppressive DTG-containing regimen (63,24,92,93,84) and rarely in patients receiving RAL (27). It reduces DTG and BIC susceptibility ~2-fold and reduces EVG susceptibility somewhat more. (4,91,30,3,10,12,67). It usually does not occur in combination with other INSTI-associated DRMs (94).
V54I is a relatively non-polymorphic mutation selected rarely in patients receiving RAL and EVG (57).
S119R is a polymorphic mutation that is weakly selected by INSTIs usually in combination with several major INSTI-associated DRMs (97). Alone, it has little, if any effect, on INSTI susceptibility (10).
- 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.11 Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Watanabe Y, Ohata Y, Doi S, Sato M, Kano M, Ikeda S and Matsuoka M. Broad anti-retroviral activity and resistance profile of a novel human immunodeficiency virus integrase inhibitor, elvitegravir (JTK-303/GS-9137). J Virol 2007.
- 2.0 2.1 2.2 2.3 2.4 McColl DJ and Chen X. Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy. Antiviral Res 2010.
- 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 Margot NA, Hluhanich RM, Jones GS, Andreatta KN, Tsiang M, McColl DJ, White KL and Miller MD. In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4. Antiviral Res 2012.
- 4.0 4.1 4.2 4.3 4.4 Mesplede T, Quashie PK, Osman N, Han Y, Singhroy DN, Lie Y, Petropoulos CJ, Huang W and Wainberg MA. Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology 2013.
- 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 Hatano H, Lampiris H, Fransen S, Gupta S, Huang W, Hoh R, Martin JN, Lalezari J, Bangsberg D, Petropoulos C and Deeks SG. Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr 2010.
- 6.0 6.1 6.2 Reuman EC, Bachmann MH, Varghese V, Fessel WJ and Shafer RW. Panel of prototypical raltegravir-resistant infectious molecular clones in a novel integrase-deleted cloning vector. Antimicrob Agents Chemother 2010.
- 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 White K, Abram ME Kulkarni R, Rhee M, Szwarcberg J and Miller, MD. Emergent drug resistance from the HIV-1 phase 3 elvitegravir/cobicistat/emtricitabine.tenofovir disoproxil fumarate studies through week 96 [Abstract 596]. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA 2013.
- 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 8.11 8.12 8.13 Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, Zhong L, Margot N, Cheng AK and Chuck SL. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis 2012.
- 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 Geretti AM, Armenia D and Ceccherini-Silberstein F. Emerging patterns and implications of HIV-1 integrase inhibitor resistance. Curr Opin Infect Dis 2012.
- 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 Abram M, Ram RR, White KL, Miller M and Callebaut C. Pre-existing HIV-1 integrase polymorphisms do not impact treatment response to elvitegravir-containing fixed-dose combination regimens in treatment-naive patients [poster number P043]. HIV Drug Therapy 2016 Glasgow 2016.
- 11.0 11.1 11.2 Quashie PK, Oliviera M, Veres T, Osman N, Han YS, Hassounah S, Lie Y, Huang W, Mesplede T and Wainberg MA. Differential effects of the G118R, H51Y, and E138K resistance substitutions in different subtypes of HIV integrase. J Virol 2015.
- 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 Smith SJ, Zhao XZ, Burke TR, Jr and Hughes SH. Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants. Retrovirology 2018.
- 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 Winters MA, Lloyd RM, Jr, Shafer RW, Kozal MJ, Miller MD and Holodniy M. Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations. PLoS One 2012.
- ^ Margot N, Cox S, Das M, McCallister S, Miller MD and Callebaut C. Rare emergence of drug resistance in HIV-1 treatment-naive patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for 144 weeks. J Clin Virol 2018.
- 15.0 15.1 15.2 15.3 Charpentier C, Karmochkine M, Laureillard D, Tisserand P, Belec L, Weiss L, Si-Mohamed A and Piketty C. Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy. HIV Med 2008.
- 16.0 16.1 Gatell JM, Katlama C, Grinsztejn B, Eron JJ, Lazzarin A, Vittecoq D, Gonzalez CJ, Danovich RM, Wan H, Zhao J, Meibohm AR, Strohmaier KM, Harvey CM, Isaacs RD and Nguyen BY. Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a Phase II study. J Acquir Immune Defic Syndr 2010.
- 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9 17.10 17.11 17.12 17.13 17.14 17.15 17.16 17.17 17.18 17.19 17.20 17.21 17.22 17.23 17.24 17.25 17.26 17.27 17.28 Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, Foster SA, Hazen RJ, Miki S, Suyama-Kagitani A, Kawauchi-Miki S, Taishi T, Kawasuji T, Johns BA, Underwood MR, Garvey EP, Sato A and Fujiwara T. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 2011.
- 18.0 18.1 18.2 18.3 18.4 18.5 18.6 18.7 18.8 Van Wesenbeeck L, Rondelez E, Feyaerts M, Verheyen A, Van der Borght K, Smits V, Cleybergh C, De Wolf H, Van Baelen K and Stuyver LJ. Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates. Antimicrob Agents Chemother 2011.
- 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9 19.10 19.11 19.12 19.13 19.14 19.15 19.16 19.17 19.18 Abram ME, Hluhanich RM, Goodman DD, Andreatta KN, Margot NA, Ye L, Niedziela-Majka A, Barnes TL, Novikov N, Chen X, Svarovskaia ES, McColl DJ, White KL and Miller MD. Impact of Primary Elvitegravir Resistance-Associated Mutations in HIV-1 Integrase on Drug Susceptibility and Viral Replication Fitness. Antimicrob Agents Chemother 2013.
- 20.0 20.1 20.2 20.3 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.
- 21.0 21.1 21.2 21.3 21.4 21.5 21.6 Goethals O, Clayton R, Van Ginderen M, Vereycken I, Wagemans E, Geluykens P, Dockx K, Strijbos R, Smits V, Vos A, Meersseman G, Jochmans D, Vermeire K, Schols D, Hallenberger S and Hertogs K. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol 2008.
- 22.0 22.1 22.2 22.3 22.4 22.5 Kobayashi M, Nakahara K, Seki T, Miki S, Kawauchi S, Suyama A, Wakasa-Morimoto C, Kodama M, Endoh T, Oosugi E, Matsushita Y, Murai H, Fujishita T, Yoshinaga T, Garvey E, Foster S, Underwood M, Johns B, Sato A and Fujiwara T. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants. Antiviral Res 2008.
- 23.0 23.1 23.2 23.3 23.4 23.5 Hurt CB, Sebastian J, Hicks CB and Eron JJ. Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009-2012. Clin Infect Dis 2014.
- 24.0 24.1 24.2 Lepik KJ, Harrigan PR, Yip B, Wang L, Robbins MA, Zhang WW, Toy J, Akagi L, Lima VD, Guillemi S, Montaner JS and Barrios R. Emergent drug resistance with integrase strand transfer inhibitor-based regimens: Incidence and risk factors. AIDS 2017.
- 25.0 25.1 25.2 25.3 25.4 25.5 25.6 25.7 25.8 25.9 25.10 Jones GS, Yu F, Zeynalzadegan A, Hesselgesser J, Chen X, Chen J, Jin H, Kim CU, Wright M, Geleziunas R and Tsiang M. Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother 2009.
- ^ Liang J, Mesplede T, Oliveira M, Anstett K and Wainberg MA. The Combination of the R263K and T66I Resistance Substitutions in HIV-1 Integrase Is Incompatible with High-Level Viral Replication and the Development of High-Level Drug Resistance. J Virol 2015.
- 27.0 27.1 27.2 27.3 27.4 27.5 27.6 27.7 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.
- 28.0 28.1 28.2 28.3 28.4 28.5 28.6 28.7 28.8 28.9 Blanco JL, Varghese V, Rhee SY, Gatell JM and Shafer RW. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 2011.
- 29.0 29.1 29.2 29.3 Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Teppler H and Nguyen BY. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008.
- 30.0 30.1 30.2 30.3 30.4 30.5 30.6 30.7 30.8 30.9 30.10 Garrido C, Villacian J, Zahonero N, Pattery T, Garcia F, Gutierrez F, Caballero E, Van Houtte M, Soriano V and de Mendoza C. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother 2012.
- 31.0 31.1 31.2 Wittkop L, Breilh D, Da Silva D, Duffau P, Mercie P, Raymond I, Anies G, Fleury H, Saux MC, Dabis F, Fagard C, Thiebaut R, Masquelier B and Pellegrin I. Virological and immunological response in HIV-1-infected patients with multiple treatment failures receiving raltegravir and optimized background therapy, ANRS CO3 Aquitaine Cohort. J Antimicrob Chemother 2009.
- 32.0 32.1 32.2 32.3 32.4 32.5 32.6 32.7 32.8 32.9 Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A, Poizot-Martin I, Richmond G, Soriano V, Ait-Khaled M, Fujiwara T, Huang J, Min S, Vavro C and Yeo J. Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study. J Infect Dis 2013.
- 33.0 33.1 33.2 33.3 33.4 33.5 33.6 33.7 33.8 33.9 33.10 Naeger LK, Harrington P, Komatsu T and Deming D. Effect of dolutegravir functional monotherapy on HIV-1 virological response in integrase strand transfer inhibitor resistant patients. Antivir Ther 2016.
- 34.0 34.1 34.2 34.3 Goethals O, Vos A, Van Ginderen M, Geluykens P, Smits V, Schols D, Hertogs K and Clayton R. Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles. Virology 2010.
- 35.0 35.1 Hachiya A, Kirby KA, Ido Y, Shigemi U, Matsuda M, Okazaki R, Imamura J, Sarafianos SG, Yokomaku Y and Iwatani Y. Impact of HIV-1 Integrase L74F and V75I Mutations in a Clinical Isolate on Resistance to Second-Generation Integrase Strand Transfer Inhibitors. Antimicrob Agents Chemother 2017.
- ^ DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, Wei X, Yale K, Szwarcberg J, White K, Cheng AK and Kearney BP. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012.
- 37.0 37.1 37.2 37.3 37.4 Seki T, Suyama-Kagitani A, Kawauchi-Miki S, Miki S, Wakasa-Morimoto C, Akihisa E, Nakahara K, Kobayashi M, Underwood MR, Sato A, Fujiwara T and Yoshinaga T. Effects of raltegravir or elvitegravir resistance signature mutations on the barrier to dolutegravir resistance in vitro. Antimicrob Agents Chemother 2015.
- 38.0 38.1 38.2 38.3 Vavro C, Hasan S, Madsen H, Horton J, DeAnda F, Martin-Carpenter L, Sato A, Cuffe R, Chen S, Underwood M and Nichols G. Prevalent polymorphisms in wild-type HIV-1 integrase are unlikely to engender drug resistance to dolutegravir (S/GSK1349572). Antimicrob Agents Chemother 2013.
- 39.0 39.1 39.2 39.3 39.4 39.5 39.6 39.7 39.8 Tsiang M, Jones GS, Goldsmith J, Mulato A, Hansen D, Kan E, Tsai L, Bam RA, Stepan G, Stray KM, Niedziela-Majka A, Yant SR, Yu H, Kukolj G, Cihlar T, Lazerwith SE, White KL and Jin H. Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile. Antimicrob Agents Chemother 2016.
- ^ 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.
- ^ Varghese V, Liu TF, Rhee SY, Libiran P, Trevino C, Fessel WJ and Shafer RW. HIV-1 integrase sequence variability in antiretroviral naive patients and in triple-class experienced patients subsequently treated with raltegravir. AIDS Res Hum Retroviruses 2010.
- ^ Delaugerre C, Flandre P, Marcelin AG, Descamps D, Tamalet C, Cottalorda J, Schneider V, Yerly S, LeGoff J, Morand-Joubert L, Chaix ML, Costagliola D and Calvez V. National survey of the prevalence and conditions of selection of HIV-1 reverse transcriptase K70E mutation. J Med Virol 2008.
- 43.0 43.1 43.2 43.3 43.4 Canducci F, Marinozzi MC, Sampaolo M, Boeri E, Spagnuolo V, Gianotti N, Castagna A, Paolucci S, Baldanti F, Lazzarin A and Clementi M. Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir. J Antimicrob Chemother 2010.
- ^ Abram ME, Ram RR, Margot NA, Barnes TL, White KL, Callebaut C and Miller MD. Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome. PLoS One 2017.
- 45.0 45.1 45.2 45.3 45.4 45.5 45.6 45.7 Fransen S, Gupta S, Danovich R, Hazuda D, Miller M, Witmer M, Petropoulos CJ and Huang W. Loss of raltegravir susceptibility of HIV-1 is conferred by multiple non-overlapping genetic pathways. J Virol 2009.
- 46.0 46.1 Kuriakose, S, George, J, Dee, N, Stoll, P, Agan, BK, Dewar, RL, Pau, A and Maldarelli, F. High Level Resistance to Dolutegravir (DTG) after Emergence of T97A Mutation. CROI 2018, Boston, MA, March 4-7 2018.
- 47.0 47.1 47.2 Brenner BG, Thomas R, Blanco JL, Ibanescu RI, Oliveira M, Mesplede T, Golubkov O, Roger M, Garcia F, Martinez E and Wainberg MA. Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors. J Antimicrob Chemother 2016.
- 48.0 48.1 Malet I, Fourati S, Charpentier C, Morand-Joubert L, Armenia D, Wirden M, Sayon S, Van Houtte M, Ceccherini-Silberstein F, Brun-Vezinet F, Perno CF, Descamps D, Capt A, Calvez V and Marcelin AG. The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. J Antimicrob Chemother 2011.
- ^ Blanco JL, Marcelin AG, Katlama C and Martinez E. Dolutegravir resistance mutations: lessons from monotherapy studies. Curr Opin Infect Dis 2018.
- 50.0 50.1 Blanco JL, Oldenbuettel C, Thomas R, Mallolas J, Wolf E, Brenner B, Spinner CD, Wainberg MA and Martinez E. Pathways of resistance in subjects failing dolutegravir monotherapy (abstract 42). 2017 Conference on Retroviruses and Opportunistic Infections, Seattle WA, USA, Feb 13-16, 2017 2017.
- ^ Wang R, Horton J, King K, Smith KY, Aboud M, Wynne B, Sievers J and Underwood M. Resistance through week 48 in the DAWNING study comparing dolutegravir (DTG) plus 2 nucleoside RT inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/r) plus 2 NRTIs in second-line treatment (Abstract THPEB071). 22nd International AIDS Conference, Amsterdam, The Netherlands, 23-27 July 2018 2018.
- ^ Vavro C, Ruel T, Wiznia A, Alvero C, Popson S, Fenton T, Hazra R, Townley E, Buchanan, A and Palumbo P. Emergence of resistance in HIV-1 Integrase (IN) following dolutegravir (DTG) treatment in 6 to 18 year old participants enrolled in the P1093 study (abstract THPEB114). 22nd International AIDS Conference, Amsterdam, The Netherlands, 23-27 July 2018 2018.
- ^ Quashie PK, Mesplede T, Han YS, Veres T, Osman N, Hassounah S, Sloan RD, Xu HT and Wainberg MA. Biochemical analysis of the role of G118R-linked dolutegravir drug resistance substitutions in HIV-1 integrase. Antimicrob Agents Chemother 2013.
- 54.0 54.1 Malet I, Gimferrer Arriaga L, Artese A, Costa G, Parrotta L, Alcaro S, Delelis O, Tmeizeh A, Katlama C, Valantin MA, Ceccherini-Silberstein F, Calvez V and Marcelin AG. New raltegravir resistance pathways induce broad cross-resistance to all currently used integrase inhibitors. J Antimicrob Chemother 2014.
- 55.0 55.1 Munir S, Thierry E, Malet I, Subra F, Calvez V, Marcelin AG, Deprez E and Delelis O. G118R and F121Y mutations identified in patients failing raltegravir treatment confer dolutegravir resistance. J Antimicrob Chemother 2015.
- ^ Hassounah SA, Alikhani A, Oliveira M, Bharaj S, Ibanescu RI, Osman N, Xu HT, Brenner BG, Mesplede T and Wainberg MA. Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1. Antimicrob Agents Chemother 2017.
- 57.0 57.1 57.2 57.3 57.4 57.5 57.6 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.
- ^ and Rowley M. The discovery of raltegravir, an integrase inhibitor for the treatment of HIV infection. Prog Med Chem 2008.
- ^ Souza Cavalcanti J, Minhoto Lanca A, de Paula Ferreira JL, da Eira M, de Souza Dantas DS and de Macedo Brigido LF. In-vivo selection of the mutation F121Y in a patient failing raltegravir containing salvage regimen. Antiviral Res 2012.
- ^ Yoshinaga T, Kobayashi M, Seki T, Miki S, Wakasa-Morimoto C, Suyama-Kagitani A, Kawauchi-Miki S, Taishi T, Kawasuji T, Johns BA, Underwood MR, Garvey EP, Sato A and Fujiwara T. Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection. Antimicrob Agents Chemother 2015.
- ^ da Silva D, Van Wesenbeeck L, Breilh D, Reigadas S, Anies G, Van Baelen K, Morlat P, Neau D, Dupon M, Wittkop L, Fleury H and Masquelier B. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemother 2010.
- 62.0 62.1 62.2 62.3 62.4 Canducci F, Ceresola ER, Boeri E, Spagnuolo V, Cossarini F, Castagna A, Lazzarin A and Clementi M. Cross-resistance profile of the novel integrase inhibitor Dolutegravir (S/GSK1349572) using clonal viral variants selected in patients failing raltegravir. J Infect Dis 2011.
- 63.0 63.1 63.2 Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, Richmond G, Buendia CB, Fourie J, Ramgopal M, Hagins D, Felizarta F, Madruga J, Reuter T, Newman T, Small CB, Lombaard J, Grinsztejn B, Dorey D, Underwood M, Griffith S, Min S and extended, Sailing Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013.
- 64.0 64.1 64.2 64.3 64.4 64.5 64.6 64.7 Fransen S, Gupta S, Frantzell A, Petropoulos CJ and Huang W. Substitutions at amino acid positions 143, 148, and 155 of HIV-1 integrase define distinct genetic barriers to raltegravir resistance in vivo. J Virol 2012.
- ^ Garrido C, Soriano V, Geretti AM, Zahonero N, Garcia S, Booth C, Gutierrez F, Viciana I and de Mendoza C. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients--impact of HIV subtypes and prior raltegravir experience. Antiviral Res 2011.
- 66.0 66.1 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.
- 67.0 67.1 67.2 67.3 67.4 67.5 67.6 Andreatta K, Chang S, Martin R, Willkom M and White KL. Integrase inhibitor resistance selections initiated with drug resistant HIV-1 (Poster 546). CROI 2018, Boston, MA, March 4-7 2018.
- ^ Oliveira M, Mesplede T, Moisi D, Ibanescu RI, Brenner B and Wainberg MA. The dolutegravir R263K resistance mutation in HIV-1 integrase is incompatible with the emergence of resistance against raltegravir. AIDS 2015.
- ^ Metifiot M, Marchand C, Maddali K and Pommier Y. Resistance to integrase inhibitors. Viruses 2010.
- ^ Delelis O, Thierry S, Subra F, Simon F, Malet I, Alloui C, Sayon S, Calvez V, Deprez E, Marcelin AG, Tchertanov L and Mouscadet JF. Impact of Y143 HIV-1 integrase mutations on resistance to raltegravir in vitro and in vivo. Antimicrob Agents Chemother 2010.
- ^ Huang W, Frantzell A, Fransen S and Petropoulos CJ. Multiple genetic pathways involving amino acid position 143 of HIV-1 integrase are preferentially associated with specific secondary amino acid substitutions and confer resistance to raltegravir and cross-resistance to elvitegravir. Antimicrob Agents Chemother 2013.
- ^ Garvey EP, Johns BA, Gartland MJ, Foster SA, Miller WH, Ferris RG, Hazen RJ, Underwood MR, Boros EE, Thompson JB, Weatherhead JG, Koble CS, Allen SH, Schaller LT, Sherrill RG, Yoshinaga T, Kobayashi M, Wakasa-Morimoto C, Miki S, Nakahara K, Noshi T, Sato A and Fujiwara T. The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral. Antimicrob Agents Chemother 2008.
- 73.0 73.1 73.2 Blanco JL, Rojas J, Paredes R, Negredo E, Mallolas J, Casadella M, Clotet B, Gatell JM, de Lazzari E, Martinez E and Team, Dolam Study. Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial. J Antimicrob Chemother 2018.
- 74.0 74.1 Parczewski M, Bander D, Urbanska A and Boron-Kaczmarska A. HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland. BMC Infect Dis 2012.
- ^ Oldenbuettel C, Wolf E, Ritter A, Noe S, Heldwein S, Pascucci R, Wiese C, Von Krosigk A, Jaegel-Guedes E, Jaeger H, Balogh A, Koegl C and Spinner CD. Dolutegravir monotherapy as treatment de-escalation in HIV-infected adults with virological control: DoluMono cohort results. Antivir Ther 2017.
- 76.0 76.1 Underwood MR, Johns BA, Sato A, Martin JN, Deeks SG and Fujiwara T. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr 2012.
- ^ Varghese V, Pinsky BA, Smith DS, Klein D and Shafer RW. Q148N, a Novel Integrase Inhibitor Resistance Mutation Associated with Low-Level Reduction in Elvitegravir Susceptibility. AIDS Res Hum Retroviruses 2016.
- ^ Fourati S, Charpentier C, Amiel C, Morand-Joubert L, Reigadas S, Trabaud MA, Delaugerre C, Nicot F, Rodallec A, Maillard A, Mirand A, Jeulin H, Montes B, Barin F, Bettinger D, Le Guillou-Guillemette H, Vallet S, Signori-Schmuck A, Descamps D, Calvez V, Flandre P, Marcelin AG and Group, Anrs Ac Resistance Study. Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a French national study of raltegravir-experienced HIV-1-infected patients. J Antimicrob Chemother 2015.
- ^ Doyle T, Dunn DT, Ceccherini-Silberstein F, De Mendoza C, Garcia F, Smit E, Fearnhill E, Marcelin AG, Martinez-Picado J, Kaiser R, Geretti AM and Group, Coronet Study. Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades. J Antimicrob Chemother 2015.
- ^ Boyd MA, Moore CL, Molina JM, Wood R, Madero JS, Wolff M, Ruxrungtham K, Losso M, Renjifo B, Teppler H, Kelleher AD, Amin J, Emery S, Cooper DA and group, Second-Line study. Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis. Lancet HIV 2015.
- 81.0 81.1 Yoshinaga T, Seki T, Miki S, Miyamoto T, Suyama-Kagitani A, Kawauchi-Miki S, Kobayashi M, Sato A, Stewart E, Underwood M and Fujiwara T. Novel secondary mutations C56S and G149A confer resistance to HIV-1 integrase strand transfer inhibitors. Antiviral Res 2018.
- ^ Low A, Prada N, Topper M, Vaida F, Castor D, Mohri H, Hazuda D, Muesing M and Markowitz M. Natural polymorphisms of human immunodeficiency virus type 1 integrase and inherent susceptibilities to a panel of integrase inhibitors. Antimicrob Agents Chemother 2009.
- 83.0 83.1 Underwood M, DeAnda F, Dorey D, Hightower K Wang F Griffith S and Horton J. Resistance post week 48 in ART-experienced integrase inhibitor-naive subjects with dolutegravir (DTG) vs. raltegravir (RAL) in SAILING (ING111762). 13th European HIV & Hepatitis Workshop, Barcelona, Spain, June 3-5, 2015 2015.
- 84.0 84.1 84.2 Wijting A Rokx C, Boucher, C, de Vries - Sluijs, D, Schurink, K, Andrinopoulou, D, van Gorp, D, Bierman, W and Rjinders, B. Dolutegravir as maintenance monotherapy for HIV-1: a randomized clinical tria (451LB)l. 2017 Conference on Retroviruses and Opportunistic Infections, Seattle WA, USA, Feb 13-16, 2017 2017.
- ^ Carganico A, Dupke S, Ehret R, Berg T, Baumgarten A, Obermeier M and Walter H. New dolutegravir resistance pattern identified in a patient failing antiretroviral therapy. J Int AIDS Soc 2014.
- ^ Hardy I, Brenner B, Quashie P, Thomas R, Petropoulos C, Huang W, Moisi D, Wainberg MA and Roger M. Evolution of a novel pathway leading to dolutegravir resistance in a patient harbouring N155H and multiclass drug resistance. J Antimicrob Chemother 2015.
- ^ Saladini F, Giannini A, Boccuto A, Tiezzi D, Vicenti I and Zazzi M. The HIV-1 integrase E157Q polymorphism per se does not alter susceptibility to raltegravir and dolutegravir in vitro. AIDS 2017.
- ^ Anstett K, Cutillas V, Fusco R, Mesplede T and Wainberg MA. Polymorphic substitution E157Q in HIV-1 integrase increases R263K-mediated dolutegravir resistance and decreases DNA binding activity. J Antimicrob Chemother 2016.
- 89.0 89.1 Charpentier C, Malet I, Andre-Garnier E, Storto A, Bocket L, Amiel C, Morand-Joubert L, Tumiotto C, Nguyen T, Maillard A, Rodallec A, Leoz M, Montes B, Schneider V, Plantier JC, Dina J, Pallier C, Mirand A, Roussel C, Signori-Schmuck A, Raymond S, Calvez V, Delaugerre C, Marcelin AG and Descamps D. Phenotypic analysis of HIV-1 E157Q integrase polymorphism and impact on virological outcome in patients initiating an integrase inhibitor-based regimen. J Antimicrob Chemother 2018.
- ^ Pham HT, Labrie L, Wijting IEA, Hassounah S, Lok KY, Portna I, Goring M, Han Y, Lungu C, van der Ende ME, Brenner BG, Boucher CA, Rijnders BJA, van Kampen JJA, Mesplede T and Wainberg MA. The S230R Integrase Substitution Associated with Viral Rebound during DTG Monotherapy Confers Low Levels INSTI Drug Resistance. J Infect Dis 2018.
- 91.0 91.1 91.2 Quashie PK, Mesplede T, Han YS, Oliveira M, Singhroy DN, Fujiwara T, Underwood MR and Wainberg MA. Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. J Virol 2012.
- ^ Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, Steimers D, Min S, Wiznia A and Team PStudy. Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093. Pediatr Infect Dis J 2015.
- ^ Taiwo BO, Zheng L, Stefanescu A, Nyaku A, Bezins B, Wallis CL, Godfrey C, Sax PE, Acosta E, Haas D, Smith KY, Sha B, Van Dam C and Gulick RM. ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)-infected Participants With HIV-1 RNA <500000 Copies/mL. Clin Infect Dis 2018.
- ^ Anstett K, Mesplede T, Oliveira M, Cutillas V and Wainberg MA. Dolutegravir resistance mutation R263K cannot coexist in combination with many classical integrase inhibitor resistance substitutions. J Virol 2015.
- ^ Wares M, Mesplede T, Quashie PK, Osman N, Han Y and Wainberg MA. The M50I polymorphic substitution in association with the R263K mutation in HIV-1 subtype B integrase increases drug resistance but does not restore viral replicative fitness. Retrovirology 2014.
- 96.0 96.1 Fun A, Van Baelen K, van Lelyveld SF, Schipper PJ, Stuyver LJ, Wensing AM and Nijhuis M. Mutation Q95K enhances N155H-mediated integrase inhibitor resistance and improves viral replication capacity. J Antimicrob Chemother 2010.
- ^ Hachiya A, Ode H, Matsuda M, Kito Y, Shigemi U, Matsuoka K, Imamura J, Yokomaku Y, Iwatani Y and Sugiura W. Natural polymorphism S119R of HIV-1 integrase enhances primary INSTI resistance. Antiviral Res 2015.
- ^ Anstett K, Brenner B, Mesplede T and Wainberg MA. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology 2017.
- ^ Ceccherini-Silberstein F, Malet I, D'Arrigo R, Antinori A, Marcelin AG and Perno CF. Characterization and structural analysis of HIV-1 integrase conservation. AIDS Rev 2009.
- ^ Wijting IEA, Lungu C, Rijnders BJA, van der Ende ME, Pham HT, Mesplede T, Pas SD, Voermans JJC, Schuurman R, van de Vijver Damc Boers PHM, Gruters RA, Boucher CAB and van Kampen JJA. HIV-1 resistance dynamics in patients failing dolutegravir maintenance monotherapy. J Infect Dis 2018.
- ^ Malet I, Subra F, Charpentier C, Collin G, Descamps D, Calvez V, Marcelin AG and Delelis O. Mutations Located outside the Integrase Gene Can Confer Resistance to HIV-1 Integrase Strand Transfer Inhibitors. MBio 2017.