Mutations to Integrase Inhibitors in real life

Transcription

1 Mutations to Integrase Inhibitors in real life González-Domenech CM, Viciana I, Sena Corrales G, Delgado M, De la Torre J, Torres Tortosa M, Téllez F, Jarilla F, Clavijo E, Santos J

2 BACKGROUND INSTI Block the step of transferring strand of viral DNA in the process of integration Raltegravir (RAL) and Elvitegravir (EVG) show a good profile of safety and virological efficacy, but modest genetic barrier to the development of resistance Dolutegravir (DTG) High genetic barrier Maintains efficacy againts resistant strains to RAL and EVG

3 Mutations in the Integrase Gene Associated With Resistance to Integrase Strand Transfer Inhibitors Dolutegravir Elvitegravir Raltegravir 2017 IAS-USA Wensing et al 2017

4 GESIDA/National AIDS Plan consensus document regarding antiretroviral treatment in adults infected with Human Immunodeficiency virus. Update January 2017 In Spain (Red de Investigación en SIDA-CoRIS: overall prevalence of primary resistance in reverse transcriptase and protease of 7,6%. The transmission of resistance to Integrase inhibitors is exceptional Determination is reserved only for cases in wich there is a high suspicion of transmission of resistance to this family A study of resistance in all patients in virological failure is recommended if the new regimen includes an INSTI

5 Aim To analyze the presence of INSTI mutations in naive patients and in those who fail with regimens that include integrase inhibitors Material and Methods We analyzed the patients with a study of genotypic resistance to INSTI between 2012 and 2016, in our reference area Trugene Siemens ViroSeq integrase (Abbot ) Junior GS 454 (Roche ) Stanford University HIV Drug Resistance Database ( db/by-mutations/)

6 RESULTS

7 RESULTS 78% males 258 patients 86 naive 82% subtype B 48 years 151 failure 21 abandonment CD4 364 cell/ul. CV 6860 copies/ml

8 NAIVE PATIENTS

9 Patient Mutation 1 V151A 2 L74M 3 E138K 4 V72I,L101I,E157Q 5 V72I,L101I 6 E138K, G193E 7 L74M 8 V72I 9 V72I 10 V72I,L101I,G118R 11 V72I, L101I 12 V72I 13 G140S, Q148R 11 men and 2 women 11 subtypes B Without accompanying mutations DTG EVG RTG 86 NAIVE patients Male Female Subtype B Subtype no B % 16%

10 Naive, L74M: 0.5% to 10% L74I: 3% to 20% of patients depending on subtype Minimal effect on susceptibility. V151A is a mutation selected in vitro. It is associated with minimally reduced susceptibility to RAL and EVG. E138K usually occur in combination with Q148 mutations. By itself does not reduce INSTI susceptibility E157Q is a polymorphic mutation. It appears to have little, if any, effect on INSTI susceptibility G118R. It has been selected in patients receiving RAL and DTG. May have impacted on the genetic barrier to DTG resistance. MUTACION DTG EVG RAL L74M V151A E138K E157Q G118R HIVdb version 8.3 (last updated )

11 PATIENTS IN FAILURE

12 Patients in failure 127 (73,4%) Male 34 (19%) First Failure 26 (15%) Second Failure >3 Failures 91(52%) 21(12%) Abandonment

13 TREATMENT AT FAILURE Treatment Patients Mutations INSTI TNF+FTC+RAL 31 6(19%) ABC+3TC+RAL 10 4(40%) ETR+RAL 6 3(50%) ETR+DRV+RAL 10 2(20%) ETR+MRV+RAL 2 1(50%) DRV+RAL 6 4(66%) DRV+MVC+RAL 3 1(33%) TNF+ddI+RAL 1 1(100%) TNF+T20+RAL 1 1(100%) TNF+EFV+RAL 1 1(100%) TNF+ETR+RAL 2 1(50%) ABC+DRV+RAL 3 1(33%) ABC+ATV+RAL 3 1(33%) ABC+ETR+RAL 2 1(50%) 3TC+EFV+RAL 2 2(100%) AZT+3TC+RAL 3 2(66%) 126 (83.4%) treatment with Raltegravir 13 (8.6%) treatment with Dolutegravir 12 (7.9 %) treatment with Elvitegravir Treatment Patients Mutations INSTI TNF+FTC+EVG/c 12 7(58%) DTG 7 4(57%) TNF+FTC+DTG 2 0 ABC+3TC+DTG 3 0 RPV+DTG 1 0

14 MUTATIONS TO FAILURE N155H/S/T 16 (35%) Q148H/K/R 16 (35%) Y143C/H/R 7 (15%) G140A/C/S 8 (17%) E92Q 7 (15%) T97A 9 (20%) V151A/Y 7 (15%) L74M 6 (13%) E138A/K 6 (13%) V72I 4 (9%) L101I 2 (4%) N155H/S/T: 1 Q148H/K/R: 1 Y143C/H/R: 2 Frequent Combinations 148H+140A/C 8 148H+138K 5 155H+151A/I 3 155H+148H 2 155H+other 8 92Q+97A 5 34/126 (26.9)% RTG 7/12 (58.3%) EVG 4/7 (57.1%) DTG 45 patients with mutations (26%) 39 patients (22.6%) had >1 major integrase mutation

15 Mutations in patients failing on Raltegravir-containing regimen (34/126 ) INSTI MUTATIONS RT/PR MUTATIONS N155H/S/T 13 (38.2%) 12 (92.3%) Q148H/K/R 13 (38.2%) 13 (100%) Y143C/H/R 6 (17.6%) 5 (83.3%) G140A/C/S 7 (20.5%) 7 (100%) E138A/K 4 (11.7%) 4 (100%) 184V (9) 215Y (3) 65R (1) 103N/S (6) 181C (4) 190A (1) 90M (5) 20 patients (58.8%) were multifailure 27 (79%) with accompanying mutations

16 Pattern of mutations at failure with Elvitegravir (TNF+FTC+EVG/c) ISNTI MUTATIONS RT/PR MUTATIONS FAILURE 1. H51Y 103N 1ºF 2.E92Q, T97A - 1ºF 3. E92Q, T97A - 2ºF 4.V72I, L101I, Y143H,N155H 184V MF 5. V72I, E92Q, T97A 67N,70E, 184V MF 6.Q95K, N155H 41L,67N,184V,118I, 215Y, 219Q MF 7. E92Q, T97A, Q148H - MF

17 Pattern of mutations at failure with Dolutegravir MUTATIONS INI MUTATIONS RT/PR 1. E138K, Q148HR NO MUTATIONS 1ºF 2. L74M, E138K, G140CS,Q148HR NO MUTATIONS MF 3. T97A,N155H, R263K NO MUTATIONS MF 4. E92Q, R263K 98S MF

18 Interpretation of resistance by the HIVDB program Raltegravir Elvitegravir Dolutegravir S I R Susceptible Potential Low level resistance Low level resistance Intermediate High level resistance 2(4.4%) 4(8.8%) 23(51%) 8(17.7%) 6 (13.3%) 20 (44.4%) 35 (77.7%) 35 (77.7%) 2(4.4%) Stanford University HIV Drug Resistance Database (

19 Conclusions. The request for studies of resistance to INSTI was made mainly to patients in therapeutic failure.. Primary mutations in naïve are infrequent (1.1%).. Selection of resistance mutations to INSTI occurs mainly in patients with virological failure, to RAL and EVG, associated with mutations of resistance to other drugs.. DTG would maintain sensitivity in more than half of patients with resistance to RAL or EVG

20 Thank you very much