Cross-resistance to integrase strand transfer
inhibitors (INSTIs) in 23 multiexperienced
Mexican patients failing to raltegravir
Orta-Reséndiz A1, Rodríguez-Díaz RA1, Hernández-Flores M1, Angulo-Medina
L2, Soto-Ramírez LE1.
1 Laborat orio
2 Complejo
de Virología Molecular, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico City, Mexico,
Hemato Oncológico y Radiocirugía/Instituto Venezolano de los Seguros Sociales IVSS, Caracas, Venezuela.
Abst#_O_05
July 16, 2016. Durban, South Africa
HIV/AIDS in México
0.2-0.3% prevalence (2014)
UNAIDS
127,823 HIV documented cases
since 1983. 82% were male.
ARV treatment coverage: 115,671
(≥15-yo patients)
INSTIs included for first line ART
in late 2015.
In salvage therapy RAL has been
used in the last 7 years.
Methods
• Retrospective data and plasma samples
from 23 multiexperienced patients failing to
RAL from 2009 to 2016.
• Plasma viral load, COBAS® AmpliPrep/COBAS®
TaqMan® HIV-1 Test, v2.0.
• Amplification and Sanger sequencing (PRRT-IN):
• ViroSeq HIV-1 Integrase Genotyping Kit.
• Integrase home-made technique.
Molecular Virology
Laboratory
Infectious Diseases
Department
v7.0
v9.1.0
Study population
Characteristics of the study population
n (%)
Male
19 (82.6)
Subtype B
23 (100)
mean
HIV-1 RNA at failure, mean log10 c/mL
4.18
CD4+ cell count, mean cells/mm3
233
Time of RAL use before failure (months)
23
Duration of prior ART (years)
Number of combinations
12.7
5
ARV drugs used with RAL
OBR (n=15)
NRTIs
NRTIs+PIs
NNRTIs+PIs
NRTIs+NNRTIs
Other
n (%)
5 (33.3)
4 (26.7)
2 (13.3)
1 (6.7)
3 (20)
In all cases RAL containing regimens were third or more advanced line of
treatment.
TDF was the most common companion to RAL.
INSTIs RAMs in RAL failing patients
RAMs were found in 13 samples
35.0
Major Primary Mutations
Major Accessory Mutations
30.4
Frequency (%)
30.0
25.0
21.7
20.0
15.0
10.0
17.4
13.0
17.4
13.0
8.7
8.7
8.7
4.3
5.0
4.3
0.0
Primary RAMSs distribution
n = 13
INSTIs predicted resistance
57
RAL
52
EVG
DTG
22
To all INSTIs
22
43
Susceptible to all INSTIs
0
10
20
30
40
Patients (%)
50
60
n = 23
70
DTG and EVG cross-resistance
RAL resistance
Resistance to other INSTIs
57%
n = 23
Resistant %
92.3%
38.4%
EVG
DTG
Comparison to RAMs combinations
decreasing response to DTG in the
VIKING-3 study
RAMs combinations after use of RAL in
the VIKING-3 study.
No INSTIs mutations
No Q148*
Q148+1 secondary mutation**
Q148+≥2 secondary mutations**
Prevalence (%)
VIKING-3
Mexico
33
43.5
36
43.5
20
8.7
11
4.3
*No Q148: Y143, N155, T66 or E92
**Secondary mutations: G140A/C/S, L74I or E138A/K/T
Castagna, A., Maggiolo, F., Penco, G., Wright, D., Mills, A., Grossberg, R., … Uhlenbrauck, G. (2014). Dolutegravir in Antiretroviral-Experienced
Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study. The Journal of Infectious Diseases,
210(3), 354–362. http://doi.org/10.1093/infdis/jiu051
Prevalence of mutations from BENCHMRK
Y143, Q148 or N155
1 of 3
Prevalence (%)
Mexico
BENCHMRK
43.5
65
2 additional combinations between the 3 mutations (8.7%)
BENCHMRK Study Teams. Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced
Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials. Clin Infect Dis. (2010) 50 (4): 605-612
DTG RAMs combinations
92Q, 138K, 74M
combinations
40%
148K/H+140S/A
60%
(n = 5)
INSTIs RAMs found according to GSS
GSS of RAL-associated regimen
Calculated GSS
More than 3
2 to 3
Less than 2
0
2
4
6
Overall total RAMs found
Rare and Miscellaneous
Major mutations
Rega v9.1.0 ©, Leuven, 29 October 2013
8
(n= 15)
10
Patients with INSTIs RAMs according to VL at
the time of failure
VL at failure (c/mL Log10)
More than 3
81.8
2 to 3
18.2
0.0
Less than 2
0.0
10.0
20.0
30.0
40.0
50.0
60.0
Patients with RAMs (%)
Rega v9.1.0 ©, Leuven, 29 October 2013
70.0
80.0
(n =12 )
90.0
Other INSTIs RAMs
• We found a high prevalence of the
L101I/T124A polymorphic
mutations combination (30.4%)
• Saladini et al. found a
prevalence of 10.8% in RAL
experienced patients(1)
• Garrido et al. found more
common in non-B subtype
(39.1%), 12.7 for subtype B(2)
1.- Saladini, F. et al. Prevalence of HIV-1 integrase mutations related to resistance
to dolutegravir in raltegravir naïve and pretreated patients. Clinical Microbiology and
Infection , Volume 18 , Issue 10 , E428 - E430
2.- Garrido et. al. Resistance associated mutations to dolutegravir (S/GSK1349572)
in HIV-infected patients – Impact of HIV subtypes and prior raltegravir experience.
Antiviral Res. 2011 Jun;90(3):164-7
Susceptible
Intermediate resistance
Resistant
Patient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
RAMs
Y143R, T97A
N155H, V151I, G163R
- (L101I/T124A)
Q148H, G140S, (L101I/T124A)
E92Q, Y143R, Y143H, L74M, E138K, L68V
Y143R, Q148H, G140S
- (L101I/T124A)
Y143H
E157Q
Q148K, E138K, G140A
Y143R, L74M, G163R
- (L101I/T124A)
E92Q, N155H, V151I, G163R, (L101I/T124A)
Y143C, N155H, S230R, (L101I/T124A)
N155H, V151I, G163R
N155H, V151I, (L101I/T124A)
HVIdb algorithm score
DTG
5
10
0
0
0
55
25
0
55
0
0
0
0
0
90
0
5
0
20
0
10
10
10
EVG
25
75
0
0
0
90
100
0
100
0
0
0
10
15
105
0
45
0
135
0
90
60
75
*Primary mutations in bold.
L101I/T/T124A combination presence in parenthesis.
HIVdb Program Genotypic Resistance Interpretation Algorithm v7.0
RAL
75
75
0
0
0
90
115
0
150
0
0
0
60
15
105
0
85
0
105
0
135
60
75
Conclusions
• This is the first study to explore integrase inhibitors resistance
profile in Mexican patients.
• From 23 included samples, 13 were resistant to RAL. All samples
were subtype B.
• From only RAL-resistant samples, 92% were resistant to EVG
and 38% to DTG.
• The 143R/H/C was the most frequent substitution found.
Conclusions
• Frequency of INSTIs RAMs combinations was lower than reported in
VIKING-3 as well as to those reported in BENCHMRK.
• We found a higher frequency of 101I/124A combination than that
reported for subtype B in some previous publications. These
polymorphisms has been suggested to play a role in the acquisition or
modulation of resistance to DTG. In our study 4 out of 7 have DTG
cross-resistance.
• While the study by Paredes et al. found no significant difference in
cross-resistance using minority variants, we will describe them in our
samples.
Acknowledgments
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Luis Enrique Soto Ramírez, MD
Biol. Roberto Rodríguez Díaz
Biol. Mario Hernández Flores
MsC. Luis A. Angulo Medina
QFB. Edder Mendoza Guadarrama
QFB. Ana Lilia López Filorio
Lab. T. Eduardo Hernández Martínez
Molecular Virology Laboratory
Infectious Diseases Department