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.

Integrase Inhibitor (INI) Resistance Notes

Last updated on March 2, 2014

Major Integrase Inhibitor (INI) Resistance Mutations
 
  66 92 138 140 143 147 148 155
Consensus T E E G Y S Q N
Raltegravir (RAL) A Q KA SA RCH   HRK H
Elvitegravir (EVG) IAK Q KA SA   G HRK H
Dolutegravir (DTG)   Q KA SA     HRK  
The table lists the most common clinically significant INI-resistance mutations. Mutations in bold red are associated with the highest levels of reduced susceptibility or virological response to the indicated INI. Mutations in bold reduce INI susceptibility or virological response. Mutations in plain text contribute to reduced suceptibility in combination with other INI-resistance mutations.

Major Primary Mutations


T66A/I/K
T66A is a nonpolymorphic mutation selected in patients receiving EVG (1,2,3) and RAL (4,5,1), usually in combination with other INI-resistance mutations. It is also selected in vitro by DTG. It reduces EVG susceptibility ~10-fold but has minimal, if any, effect on RAL or DTG susceptibility (6,7,8,9,10).

T66I is a nonpolymorphic mutation selected in vitro (11,12,13,7,14) and in patients receiving EVG (11,12,13,15,3). T66I reduces EVG susceptibility by ~15-fold (6,7,16,8,9) but does not reduce RAL (6,16,7,8,10) or DTG (9) susceptibility.

T66K is a nonpolymorphic mutation selected in vitro (7) and in patients (2) receiving EVG. It is associated with 40- to 80-fold reduced EVG susceptibility (6,7,9), 10- to 20-fold reduced RAL susceptibility (6,7,9) and 2-fold reduced DTG susceptibility (6,9).


E92Q/G/V
E92Q is a nonpolymorphic mutation selected in patients receiving RAL (17,1,15,3) and EVG (1,2,18,15). It reduces RAL susceptibility 5 to 10-fold (6,16,8,9) and EVG susceptibility ~30-fold (12,6,16,8,9). It is often the primary INI-resistance mutation associated with virological failure on an EVG-containing regimen (15,3). It is selected in vitro by DTG and reduces DTG susceptibility ~1.5-fold (6,9).

E92G is a nonpolymorphic mutation selected in vitro (7) and in vivo by EVG (3,9). It reduces EVG susceptibility ~10-fold (7,9) but does not reduce RAL or DTG susceptibility (7,9).

E92V has been selected solely in vitro with the investigational INI GS-9160. It reduces RAL and EVG susceptibility 10 and 40-fold, respectively (16).


Y143C/R/K/H/S/G/A
Y143C/R are nonpolymorphic mutations selected by RAL (19,17,20,21,22,19,23,24). Alone, Y143C and Y143R reduce RAL susceptibility by ~5 and 20-fold respectively (17,22,25,19,24) but in combination with T97A or other accessory mutations, they reduce RAL susceptibility >100-fold (26,19,17,22). Y143H is a less common mutation at this position. It is likely a transitional mutation between the wildtype Y and the 2-base pair mutant R. Alone, Y143C/R mutations have minimal effects on EVG susceptibility (6,9,24,8). However, in combination with >=2 accessory INI-resistance mutations (such as L74M, T97A, G163R, and S230R) they are associated with a 10 to 20-fold reduction in EVG susceptibility (27). Y143 mutations do not reduce DTG susceptibility (24,10,8).

Additional extremely rare mutations at this position have been observed in RAL-treated patients and shown to reduce RAL susceptibility by 5 to 10-fold including Y143K/S/G/A (27,25).

S147G
S147G is a nonpolymorphic mutation selected in patients receiving EVG (2,3). It reduces EVG susceptibility 5 to 10-fold but has minimal if any effect on RAL susceptibility (7,12,8,9).

Q148HKR
Q148H/K/R are nonpolymorphic mutations selected in patients receiving RAL and EVG (28,19,3,1,26,21,24,29,30,4,31). Alone, Q148H reduces RAL and EVG susceptibility 5 to 10-fold and Q148R/K reduce RAL and EVG susceptibility 30 to 100-fold (26,6,9,13,32,24,25). In combination with G140S/A, Q148H/R/K reduce RAL and EVG susceptibility >100-fold. (26,6,9,13,32,24,25). Alone, Q148H/K/R have minimal effects on DTG susceptibility (6,33,9). However, in combination with E138K/A G140S/A they cause >10-fold reduced DTG susceptibility (6,34,33,9).

N155HST
N155H is a nonpolymorphic mutation selected in patients receiving RAL and EVG (28,19,3,1,26,21,24,29,30,4,2,15,3,35,31). Alone, it reduces RAL susceptibility ~15-fold and EVG susceptibility ~30-fold (6,7,16,19,8,26). Susceptibility is further reduced when N155H occurs in combination with E92Q and other primary or accessory INI-resistance mutations. N155H has been selected by DTG in RAL-experienced patients (34) but does not reduce DTG susceptibility by itself (6,33). N155S/T are rare nonpolymorphic mutations selected in vitro by investigational INIs. N155S/T reduce RAL and EVG susceptibility somewhat less than N155H (6,16,10,6).


Major Accessory Mutations

H51Y
H51Y is an uncommon nonpolymorphic accessory mutation selected in vitro by EVG (12,11,7) and DTG (36) and in patients receiving RAL (1,37) and EVG (15). It appears to increase IN activity nonspecifically by increasing affinity for LTR (38). It reduces EVG susceptibility by ~2 to 3-fold (12,7,36,22). Although alone it does not influence DTG susceptibility, the combination of H51Y and R263K reduces DTG susceptibility ~5-fold. H51Y does not appear to reduce RAL susceptibility (7,36).

L74M
L74M is a polymorphic accessory INI-resistance mutation selected in patients receiving RAL (17,28,24,30,31), EVG (1), and DTG (34). Alone, it does not reduce INI susceptibility. But when it occurs in combination with other INI-resistance mutations, L74M contributes to reduced RAL, EVG, and DTG susceptibility (16,32,39,14).

T97A
T97A is a polymorphic accessory INI-resistance mutation that (depending on subtype) occurs in 1% to 5% of viruses from untreated persons. It is selected by RAL (40,21,37,3,31) and EVG (3). Alone, it has minimal if any effect on INI susceptibility but it markedly reduces RAL susceptibility in combination with Y143C/R (27,26). T97A also appears to be selected by DTG in patients previously treated with RAL (34).

E138KA
E138K/A are nonpolymorphic accessory resistance mutations selected in patients receiving RAL (17,41,31), EVG (2), and DTG (34). They usually occur in combination with Q148 mutations. Alone they do not reduce INI susceptibility (11,16), however they are associated with >100-fold reduced RAL and EVG susceptibility and up to 10-fold reduced DTG susceptibility when they occur in combination with Q148 mutations (34,42,33,39).

E138D is a polymorphism that occurs in 1% to 2% of viruses from INI-naive patients. It does not appear to be selected by INIs or to reduce INI susceptibility (43).

G140SAC
G140S/A/C are nonpolymorphic mutations that usually occur with Q148 mutations in patients receiving RAL (17,19,1,24,21,4,31) and EVG (2,15). Aone, they do not reduce INI susceptibility. However, in combination with Q148 mutations, they are associated with a >100-fold reduction in RAL and EVG susceptibility and up to a 10-fold reduction in DTG susceptibility (42,44,35).

V151ILA
V151I is a polymorphic accessory INI-resistance mutation occurring in 1% to 6% of viruses depending on subtype. It is selected in patients receiving RAL (17) and in vitro by EVG (14). It appears to have little or no effect on INI susceptibility (45). V151L is an extremely rare nonpolymorphic mutation selected in vitro by early investigational INIs but not in patients receiving INIs. It reduces susceptibility to RAL, EVG, and DTG by ~10, ~40, and 3.6-fold, respectively (6). V151A is an extremely rare nonpolymorphic mutation selected in vitro by an investigational INI. It has been reported to reduce susceptibility to RAL by 4-fold and to EVG by 12-fold (16).

S153YF
S153Y/F are extremely rare nonpolymorphic mutations selected in vitro by EVG (S153Y) (7,12) and DTG (S153Y/F) (6,6). S153Y/F reduce RAL and DTG susceptibility ~2-fold and EVG susceptibility by ~4-fold (6,46,33).

G163RK
G163R/K are nonpolymorphic in all subtypes except subtype F (43). They are commonly selected in patients receiving RAL (17,5,28,31). Their effect on INI susceptibility has not been well studied. G163E/Q/A are polymorphisms that do not appear to be selected by INIs.

S230R
S230R is a nonpolymorphic accessory mutation selected in vitro and in vivo by RAL (17) and in vitro by EVG (13). It appears to have minimal if any effect on INI susceptibility (13). S230N is a polymorphism that is not associated with reduced INI susceptibility.

R263K
R263K is a nonpolymorphic mutation selected in patients receiving RAL (17) and DTG (47) and in vitro by EVG (7) and DTG (36,48). It reduces RAL, DTG and EVG susceptibility 2-fold, 2-fold, and 3 to 5-fold, respectively (36,48,24,7)(47).


Rare Primary INI-Resistance Mutations

G118R
G118R is an extremely rare nonpolymorphic mutation that has been selected by RAL in a patient with a CRF02_AG virus (49). When G118R occurred in combination with L74M in this virus, RAL susceptibility was reduced by ~10-fold and EVG susceptibility by ~3-fold (14,49,22). G118R has been selected in vitro by DTG and reported to reduce DTG susceptibility by 3-fold in a biochemical assay (48,38).

F121Y
F121Y is a nonpolymorphic mutation that is selected in vitro by RAL (50) and EVG (12) and in one patient receiving RAL (51). It reduces susceptibility to RAL by about 5-fold and to EVG by about 10-fold (12,14,22). It does not appear to reduce DTG susceptibility.

P145S
P145S is a rare nonpolymorphic mutation that has been selected in vitro by EVG (52) and in vivo by EVG (2). It causes high-level resistance to EVG (14).

Q146P
Q146P is a rare nonpolymorphic mutation that has been selected in vitro by EVG (12). It reduces EVG susceptibility by about 10-fold (12).


Miscellaneous INI-Associated Mutations


V54I is a minimally polymorphic mutation selected in vitro (32) and rarely in vivo (43) by RAL.

L68V is a polymorphic accessory mutation that has been reported in patients receiving EVG (1,11,15). It may synergistically reduce EVG susceptibility in combination with E92Q (11).

Q95K is a nonpolymorphic accessory INI-resistance mutation selected in patients receiving RAL and in vitro by EVG (53,17). Alone, it has little if any effect on INI susceptibility (12,53).

H114Y is an extremely rare nonpolymorphic mutation selected in vitro by EVG (13).

A128T is a nonpolymorphic mutation selected in vitro by EVG. It does not appear to reduce INI susceptibility (13).

E157Q is a polymorphic mutation that is weakly selected in patients receiving RAL (40,31) and in vitro by EVG (12). E157Q reduces RAL susceptibility by about 5-fold and EVG susceptibility by about 2-fold (32,22)

REFERENCES

  1. 1. Hatano H, Lampiris H, Fransen S, Gupta S, Huang W, Hoh R, Martin JN, Lalezari J, Bangsberg D, Petropoulos C, Deeks SG. Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr 2010.
  2. 2. Winters MA, Lloyd RM Jr, Shafer RW, Kozal MJ, Miller MD, Holodniy M. Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations. PLoS One 2012.
  3. 3. Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, Zhong L, Margot N, Cheng AK, 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.
  4. 4. Charpentier C, Karmochkine M, Laureillard D, Tisserand P, Belec L, Weiss L, Si-Mohamed A, Piketty C. Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy. HIV Med 2008.
  5. 5. 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, 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.
  6. 6. 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, Fujiwara T. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 2011.
  7. 7. Margot NA, Hluhanich RM, Jones GS, Andreatta KN, Tsiang M, McColl DJ, White KL, Miller MD. In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4. Antiviral Res 2012.
  8. 8. Van Wesenbeeck L, Rondelez E, Feyaerts M, Verheyen A, Van der Borght K, Smits V, Cleybergh C, De Wolf H, Van Baelen K, 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.
  9. 9. 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, Miller MD. Impact of Primary Elvitegravir Resistance-Associated Mutations in HIV-1 Integrase on Drug Susceptibility and Viral Replication Fitness. Antimicrob Agents Chemother 2013.
  10. 10. Van der Borght K, Verheyen A, Feyaerts M, Van Wesenbeeck L, Verlinden Y, Van Craenenbroeck E, van Vlijmen H. Quantitative prediction of integrase inhibitor resistance from genotype through consensus linear regression modeling. Virol J 2013.
  11. 11. McColl DJ, Chen X. Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy. Antiviral Res 2010.
  12. 12. Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Watanabe Y, Ohata Y, Doi S, Sato M, Kano M, Ikeda S, 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.
  13. 13. 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, 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.
  14. 14. 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, Fujiwara T. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants. Antiviral Res 2008.
  15. 15. White K, Abram ME, Kulkarni R, Rhee M, Szwarcberg J, 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.
  16. 16. Jones GS, Yu F, Zeynalzadegan A, Hesselgesser J, Chen X, Chen J, Jin H, Kim CU, Wright M, Geleziunas R, Tsiang M. Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother 2009.
  17. 17. Blanco JL, Varghese V, Rhee SY, Gatell JM, Shafer RW. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 2011.
  18. 18. DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, Wei X, Yale K, Szwarcberg J, White K, Cheng AK, 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.
  19. 19. Fransen S, Gupta S, Frantzell A, Petropoulos CJ, 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.
  20. 20. Metifiot M, Marchand C, Maddali K, Pommier Y. Resistance to integrase inhibitors. Viruses 2010.
  21. 21. Canducci F, Marinozzi MC, Sampaolo M, Boeri E, Spagnuolo V, Gianotti N, Castagna A, Paolucci S, Baldanti F, Lazzarin A, Clementi M. Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir. J Antimicrob Chemother 2010.
  22. 22. Geretti AM, Armenia D, Ceccherini-Silberstein F. Emerging patterns and implications of HIV-1 integrase inhibitor resistance. Curr Opin Infect Dis 2012.
  23. 23. Delelis O, Thierry S, Subra F, Simon F, Malet I, Alloui C, Sayon S, Calvez V, Deprez E, Marcelin AG, Tchertanov L, Mouscadet JF. Impact of Y143 HIV-1 integrase mutations on resistance to raltegravir in vitro and in vivo. Antimicrob Agents Chemother 2010.
  24. 24. Garrido C, Villacian J, Zahonero N, Pattery T, Garcia F, Gutierrez F, Caballero E, Van Houtte M, Soriano V, de Mendoza C. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother 2012.
  25. 25. Canducci F, Ceresola ER, Boeri E, Spagnuolo V, Cossarini F, Castagna A, Lazzarin A, 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.
  26. 26. Fransen S, Gupta S, Danovich R, Hazuda D, Miller M, Witmer M, Petropoulos CJ, Huang W. Loss of raltegravir susceptibility of HIV-1 is conferred by multiple non-overlapping genetic pathways. J Virol 2009.
  27. 27. Huang W, Frantzell A, Fransen S, 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.
  28. 28. 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, Nguyen BY. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008.
  29. 29. Parczewski M, Bander D, Urbanska A, Boron-Kaczmarska A. HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland. BMC Infect Dis 2012.
  30. 30. 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, 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.
  31. 31. Hurt CB, Sebastian J, Hicks CB, Eron JJ. Resistance to HIV Integrase Strand Transfer Inhibitors Among Clinical Specimens in the United States, 2009-2012. Clin Infect Dis 2014.
  32. 32. Goethals O, Vos A, Van Ginderen M, Geluykens P, Smits V, Schols D, Hertogs K, 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.
  33. 33. Underwood MR, Johns BA, Sato A, Martin JN, Deeks SG, Fujiwara T. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr 2012.
  34. 34. 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, 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.
  35. 35. Brenner BG, Lowe M, Moisi D, Hardy I, Gagnon S, Charest H, Baril JG, Wainberg MA, Roger M. Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors. J Med Virol 2011.
  36. 36. Mesplede T, Quashie PK, Osman N, Han Y, Singhroy DN, Lie Y, Petropoulos CJ, Huang W, Wainberg MA. Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology 2013.
  37. 37. Reuman EC, Bachmann MH, Varghese V, Fessel WJ, Shafer RW. Panel of prototypical raltegravir-resistant infectious molecular clones in a novel integrase-deleted cloning vector. Antimicrob Agents Chemother 2010.
  38. 38. Quashie PK, Mesplede T, Han YS, Veres T, Osman N, Hassounah S, Sloan RD, Xu HT, Wainberg MA. Biochemical analysis of the role of G118R-linked dolutegravir drug resistance substitutions in HIV-1 integrase. Antimicrob Agents Chemother 2013.
  39. 39. Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, Molina JM, Chas J, Durant J, Moreno S, Doroana M, Ait-Khaled M, Huang J, Min S, Song I, Vavro C, Nichols G, Yeo JM, for the Viking-Study Group. Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study. J Infect Dis 2014.
  40. 40. Malet I, Delelis O, Valantin MA, Montes B, Soulie C, Wirden M, Tchertanov L, Peytavin G, Reynes J, Mouscadet JF, Katlama C, Calvez V, Marcelin AG. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 2008.
  41. 41. 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, Masquelier B. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemother 2010.
  42. 42. Underwood M, Vavro C, Haney R, Horton J. Epidemiology of dolutegravir resistance in ~700 raltegravir-resistant isolates. International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies 2013.
  43. 43. Rhee SY, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer RW. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 2003.
  44. 44. Garrido C, Soriano V, Geretti AM, Zahonero N, Garcia S, Booth C, Gutierrez F, Viciana I, 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.
  45. 45. Low A, Prada N, Topper M, Vaida F, Castor D, Mohri H, Hazuda D, Muesing M, Markowitz M. Natural polymorphisms of human immunodeficiency virus type 1 integrase and inherent susceptibilities to a panel of integrase inhibitors. Antimicrob Agents Chemother 2009.
  46. 46. Vavro C, Hasan S, Madsen H, Horton J, DeAnda F, Martin-Carpenter L, Sato A, Cuffe R, Chen S, Underwood M, Nichols G. Prevalent polymorphisms in wild-type HIV-1 integrase are unlikely to engender drug resistance to dolutegravir (S/GSK1349572). Antimicrob Agents Chemother 2013.
  47. 47. 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. 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.
  48. 48. Quashie PK, Mesplede T, Han YS, Oliveira M, Singhroy DN, Fujiwara T, Underwood MR, 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.
  49. 49. 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, Marcelin AG. The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. J Antimicrob Chemother 2011.
  50. 50. Rowley M. The discovery of raltegravir, an integrase inhibitor for the treatment of HIV infection. Prog Med Chem 2008.
  51. 51. Souza Cavalcanti J, Minhoto Lanca A, de Paula Ferreira JL, da Eira M, de Souza Dantas DS, de Macedo Brigido LF. In-vivo selection of the mutation F121Y in a patient failing raltegravir containing salvage regimen. Antiviral Res 2012.
  52. 52. 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, Fujiwara T. The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral. Antimicrob Agents Chemother 2008.
  53. 53. Fun A, Van Baelen K, van Lelyveld SF, Schipper PJ, Stuyver LJ, Wensing AM, Nijhuis M. Mutation Q95K enhances N155H-mediated integrase inhibitor resistance and improves viral replication capacity. J Antimicrob Chemother 2010.