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Integrase strand transfer inhibitors


Mutations associated with resistance Mutations associated with « possible resistance »
RAL
 T66A/K [10,40]
E92Q [1, 2]
 G118R [10,17]
 F121Y [10,17]
 G140A/S [7]
 Y143A/C/G/H/R/S [1, 3, 4, 5, 8, 14]
 N144D [42]
 Q148E/G/H/K/R [1, 2]
 V151L [9]
 N155H/S/T [1, 2, 9]
 E157Q [2]
 S230R [18, 31, 32, 33]
 R263K [16,18]
 L74F/I + V75I [36]

EVG  T66A/I/K [6]
 E92Q [6]
 T97A [19, 20]
 G118R [17]
 F121Y [9,17]
 E138K
 G140A/C/S [34, 41]
 Y143A/C/G/H/R/S [14]
 N144D [42]
 P145S [9]
 S147G [19]
 Q148E/G/H/K/R [6]
 V151L [9]
 N155H/S/T [6, 9]
 E157Q [11,35]
 S230R [18, 31, 32, 33]
 R263K [18]

 L74F/I + V75I [36]


DTG*
50 mg QD

 G118R [12,13]
 F121Y [17]
 E138A/K/T [15]
 G140A/C/S [15]
 N144D [42]
 Q148H/K/R
 V151L [9, 23]
 S153F/Y [9, 23, 26, 34]
 N155H [18]
 S230R [29]
 R263K [16]
 T66K + L74M [9]
 L74I + E92Q [30]

 T66K [9]
DTG*
50 mg BID
G118R [12,13]
F121Y [17]
N144D [42]
V151L [9,23]
S153F/Y [9, 23, 26, 34]
R263K [16]
T66K + L74M [9]
E92Q + N155H [9, 21, 22]
Q148H/K/R + at least 2 mutations among: L74I or T97A or E138A/K/T or G140A/C/S [15, 38, 39]
Q148H/K/R + N155H [9, 27,28]
T66K [9]
Q148H/K/R + 1 mutation among: L74I or E138A/K/T or G140A/C/S [15]
CAB**  G118R [12,13]
 F121Y [17]
 E138A/K/T
 G140A/C/R/S [37]
 N144D [42]
 Q148H/K/R [15]
 V151L [9, 23]
 S153F/Y [9, 23, 26, 34]
 N155H [18]
 S230R [29]
 R263K [16]
 T66K + L74M [9]
 L74I + E92Q [30]
 T66K [9]
BIC**  G118R [12,13]
 F121Y [17]
 E138A/K/T
 G140A/C/S
 N144D [42]
 Q148H/K/R
 V151L [9, 23]
 S153F/Y [9, 23, 26, 34]
 N155H [18]
 S230R [29]
 R263K [16]
 T66K + L74M [9]
 L74I + E92Q [30]
 T66K [9]

RAL: raltegravir, EVG: elvitegravir, DTG: dolutegravir, CAB: cabotegravir, BIC: bictegravir.
* Please note that rules are different for DTG 50 mg BID and 50 mg QD.
**Due to few data and to the very close structures of dolutegravir, cabotegravir and bictegravir some rules for dolutegravir QD are transposed to cabotegravir and bictegravir.

For DNA provirus, impact of stop codons and G->A mutations on ARV resistance is unknown

1/ Cooper DA et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008 Jul 24;359(4):355-65.

2/ Malet I et al. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother. 2008 Apr;52(4):1351-8.

3/ Hatano H et al. Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2010 Aug 1;54(4):389-93.

4/ Da Silva D et al. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemother. 2010 Jun;65(6):1262-9.

5/ Ceccherini-Silberstein F et al. Virological response and resistance in multi-experienced patients treated by raltegravir. XVII International HIV drug resistance workshop : basic principles and clinical implications, 10-14 June 2008, Sitges, Spain, abstract 18.

6/ Waters J et al. Evolution of resistance to the HIV integrase inhibitor (INI) elvitegravir can involve genotypic switching among primary INI resistance patterns. XVII International HIV drug resistance workshop : basic principles and clinical implications, 9-13 June 2009, Fort Myers, Florida, abstract 116.

7/ Geretti AM et al. Prevalence and patterns of raltegravir resistance in treated patients in Europe. Antiviral Therapy 2010; 15 Suppl 2: A62 (abstract 51)

8/ Huang W et al. Identification of alternative amino acid substitutions at HIV-1 integrase codon 143 that confer reduced susceptibility to raltegravir. 18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston, USA, abstract 607.

9/ Kobayashi M et al. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011 Feb;55(2):813-21.

10/ Malet I et al. The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. J Antimicrob Chemother. 2011 Dec;66(12):2827-30.

11/ White K et al. Integrated Analysis of Emergent Drug Resistance from the HIV-1 Phase 3 QUAD Studies through Week 48. International Workshop on HIV & Hepatitis Virus Drug Resistance and CurativeStrategies June 5-9, 2012 Sitges, Spain, Abstract 4.

12/ Bar-Magen et al. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol. 2010 Sep;84(18):9210-6.

13/ Hare S et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72.

14/ Huang W et al. Contribution of raltegravir selected secondary mutations to reduction in elvitegravir susceptibility of patient-derived HIV integrase containing Y143 mutations. International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies June 4-8, 2013 Toronto, Canada, Abstract 89.

15/ Vavro CL et al. Integrase genotypic and phenotypic predictors of antiviral response to dolutegravir (DTG) in subjects with resistance to integrase inhibitors (INIs). International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies June 4-8, 2013 Toronto, Canada, Abstract 29.

16/ Underwood MR et al. Analysis and characterization of treatment-emergent resistance in ART-experienced, integrase inhibitor-naive subjects with dolutegravir (DTG) versus raltegravir (RAL) in SAILING (ING111762). International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies June 4-8, 2013 Toronto, Canada, Abstract 21.

17/ Malet I et al. New raltegravir resistance pathways induce broad cross-resistance to all currently used integrase inhibitors. J Antimicrob Chemother. 2014 Aug;69(8):2118-22.

18/ Underwood MR et al. Resistance Post Week 48 in ART-Experienced, Integrase Inhibitor-Naïve Subjects with Dolutegravir (DTG) vs. Raltegravir (RAL) in SAILING (ING111762). 13th European HIV & Hepatitis workshop, june 3-5 2015, Barcelona, Spain (Abstract n°6).

19/ Molina et al. 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 Jan;12(1):27-35.

20/ Sax et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012 Jun 30;379(9835):2439-48.

21/ Underwood et al.The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):297-301.

22/ Frantzell et al. Dolutegravir resistance requires multiple primary mutation in HIV-1 integrase. CROI 2015. Abstract Number: 121.

23/ Yoshinoga et al. Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection. Antimicrob Agents Chemother. 2015 Jan;59(1):397-406

24/ Margolis et al. 744 and Rilpivirine As Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. CROI 2014. Abstract Number: 91LB

25/ Dudas et al. Characterization of NNRTI and INI Resistance Mutations Observed in a Study Subject on Oral Two-Drug Maintenance Therapy with 10 mg Cabotegravir + 25 mg Rilpivirine. IHDRW 2015 Seattle, WA, USA. Abstract 13.

26/ Abram ME, Ram RR, White KL, Miller MD, Callebaut C. Pre-existing HIV-1 integrase polymorphisms do not impact treatment response to elvitegravir-containing fixed-dose combination regimens in treatment-naive patients. HIV Drug Therapy 2016 Glasgow. The poster can be found at:
http://s3-eu-west-1.amazonaws.com/hivglasgow/wp-content/uploads/2016/12/07153921/3.-Treatment-Strategies-Target-Populations_Poster-Book.pdf

27/ Huang W et al. Impact of Raltegravir/Elvitegravir Selected Mutations on Dolutegravir Cross-resistance. CROI March 3-6, 2014, Boston, MA, USA. Abstract 595.

28/ Blanco JL et al. Pathways of resitance in subjects failing dolutegravir monotherapy. CROI February 13–16, 2017, Seattle, WA, USA. Abstract 42

29/ Wijting I et al. Dolutegravir as maintenance monotherapy for HIV-1: a randomized clinical trial. CROI February 13–16, 2017, Seattle, WA, USA. Abstract LB451

30/ Katlama C et al. Dolutegravir as monotherapy in HIV-1-infected individuals with suppressed HIV viraemia. J Antimicrob Chemother. 2016 Sep;71(9):2646-50

31/ Goethals O et al. 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 Nov;82(21):10366-74.

32/ Blanco JL et al. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis. 2011 May 1;203(9):1204-14.

33/ Pham HT et al. Characterization of the dolutegravir monotherapy-acquired S230R resistance mutation. CROI March 4-7, 2018, Boston, MA, USA. Abstract 548.

34/ Andreatta K et al. Integrase inhibitor resistance selections initiated with drug resistant HIV-1. CROI March 4-7, 2018, Boston, MA, USA. Abstract 546.

35/ Charpentier C et al. 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 Apr 1;73(4):1039-1044.

36/ Hachiya A et al. Impact of clinically observed integrase mutations on dolutegravir. CROI February 13–16, 2017, Seattle, WA, USA. Abstract 496.

37/ Orkin C et al. Long-acting CABOTEGRAVIR + RILPIVIRINE for HIV maintenance: FLAIR Week 48 results. CROI 2019, Seattle, WA, USA. Abs. 140LB.

38/ George JM et al. Rapid Development of High-Level Resistance to Dolutegravir With Emergence of T97A Mutation in 2 Treatment-Experienced Individuals With Baseline Partial Sensitivity to Dolutegravir. Open Forum Infect Dis. 2018 Sep 8;5(10):221.

39/ White K et al. Potent activity of GS-9883, a novel unboosted HIV-1 integrase strand transfer inhibitor (INSTI), against patients isolates with ISNTI-resistance. 14th European HIV & Hepatitis workshop, May 2016, Roma, Italy (Abstract 0_1).

40/ Margot NA et al. In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4.
Antiviral Res. 2012 Feb;93(2):288-296.

41/ Goethals O et al. 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 Jul 5;402(2):338-46.

42/ Andreatta K et al. Long-term Bictegravir and Dolutegravir Resistance Selections Initiated with HIV-1 Containing M184V in Reverse Transcriptase. Abstract 9. European Meeting on HIV & Hepatitis 2020.