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

BACKGROUNDINSTI

Block the step of transferring strand of

viral DNA in the processof 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 againtsresistant strains to RAL

and EVG

Mutations in the Integrase Gene Associated With Resistance to Integrase Strand Transfer Inhibitors

Dolutegravir

Elvitegravir

Raltegravir

2017 IAS-USA Wensing et al 2017

GESIDA/National AIDS Plan consensus document regardingantiretroviral treatment in adults infected with Human

Immunodeficiency virus. Update January 2017

In Spain (Red de Investigación en SIDA-CoRIS: overall prevalence ofprimary 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 highsuspicion of transmission of resistance to this family

A study of resistance in all patients in virological failure isrecommended if the new regimen includes an INSTI

Aim

To analyze the presence of INSTI mutations in naive patients and in those

who fail with regimens that includeintegrase inhibitors

Material and Methods

We analyzed the patients with a studyof genotypic resistance to INSTI

between 2012 and 2016, in ourreference area

Trugene Siemens®

ViroSeq integrase (Abbot®)Junior GS 454 (Roche®)

Stanford University HIV Drug Resistance Database

(https://hivdb.stanford.edu/hivdb/by-mutations/)

RESULTS

RESULTS

258 patients

86 naive

151 failure

21 abandonment

78% males

48 years

CV 6860 copies/mL

CD4 364 cell/ul.

82%

subtype B

NAIVE PATIENTS

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

86 NAIVE patients

Male

Female

74

12

Subtype B

Subtype no B

84%

16%

11 men and 2 women11 subtypes B

Without accompanyingmutations

DTG

EVG

RTG

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 minimallyreduced susceptibility to RAL and

EVG.

E138K usually occur in combinationwith Q148 mutations. By itself does

not reduce INSTI susceptibility

E157Q is a polymorphic mutation. Itappears to have little, if any, effect on

INSTI susceptibility

G118R. It has been selected in patients receivingRAL and DTG. May have impacted on the geneticbarrier to DTG resistance

MUTACION DTG EVG RAL

L74M 0 0 0

V151A 0 30 15

E138K 10 15 15

E157Q 0 10 10

G118R 15 30 30.HIVdb version 8.3 (last updated 2017-03-02)

PATIENTS IN FAILURE

34

(19%)

91(52%)

26 (15%)

21(12%)

First Failure

Second Failure

Abandonment>3 Failures

Patients in failure

127 (73,4%)Male

Treatment Patients MutationsINSTI

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%)

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

TREATMENT AT FAILURE

126 (83.4%) treatment with Raltegravir13 (8.6%) treatment with Dolutegravir12 (7.9 %) treatment with Elvitegravir

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%)

45 patients with mutations (26%)39 patients (22.6%) had >1 major integrase mutation

FrequentCombinations

148H+140A/C 8

148H+138K 5

155H+151A/I 3

155H+148H 2

155H+other 8

92Q+97A 5

N155H/S/T: 1Q148H/K/R: 1Y143C/H/R: 2

34/126 (26.9)% RTG7/12 (58.3%) EVG4/7 (57.1%) DTG

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%)

20 patients (58.8%) were multifailure

27 (79%) with accompanying mutations

184V (9)215Y (3)65R (1)

103N/S (6)181C (4)190A (1)90M (5)

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

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

Interpretation of resistance by theHIVDB program

Raltegravir Elvitegravir Dolutegravir

SSusceptible

Potential Lowlevel resistance

2(4.4%) 4(8.8%) 23(51%)

ILow levelresistance

Intermediate

8(17.7%) 6 (13.3%) 20 (44.4%)

RHigh levelresistance

35 (77.7%) 35 (77.7%) 2(4.4%)

Stanford University HIV Drug Resistance Database (https://hivdb.stanford.edu/hivdb/by-mutations/)

Conclusions

. The request for studies of resistance to INSTI was mademainly to patients in therapeutic failure.

. Primary mutations in naïve are infrequent (1.1%).

. Selection of resistance mutations to INSTI occurs mainly inpatients with virological failure, to RAL and EVG, associatedwith mutations of resistance to other drugs.

. DTG would maintain sensitivity in more than half of patientswith resistance to RAL or EVG

Thank you very much